1,3-thiazol-2-yl substituted benzamides

ABSTRACT

The present invention relates to 1,3-thiazol-2-yl substituted benzamide compounds of general formula (I) as described and defined herein, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neurogenic disorder, as a sole agent or in combination with other active ingredients.

This application is the U.S. national phase of International ApplicationNo. PCT/EP2015/078765, filed Dec. 2015, which designated the U.S. andclaims priority to Application No. EP 14196954.3, filed 9 Dec. 2014; theentire contest of each of which are hereby incorporated by reference.

The present invention relates to 1,3-thiazol-2-yl substituted benzamidecompounds of general formula (I) as described and defined herein, topharmaceutical compositions and combinations comprising said compoundsand to the use of said compounds for manufacturing a pharmaceuticalcomposition for the treatment or prophylaxis of a disease, in particularof neurogenic disorder, as a sole agent or in combination with otheractive ingredients.

BACKGROUND OF THE INVENTION

The present invention relates to chemical compounds that inhibit P2X3receptor. P2X purinoceptor 3 is a protein that in humans is encoded bythe P2RX3 gene (Garcia-Guzman M, Stuhmer W, Soto F (September 1997).“Molecular characterization and pharmacological properties of the humanP2X3 purinoceptor”. Brain Res Mol Brain Res 47 (1-2): 59-66). Theproduct of this gene belongs to the family of purinoceptors for ATP.This receptor functions as a ligand-gated ion channel and transducesATP-evoked nociceptor activation.

P2X purinoreceptors are a family of ligand-gated ion channels that areactivated by ATP. To date, seven members of this family have beencloned, comprising P2X1-7 [Burnstock 2013, front Cell Neurosci 7:227].These channels can exist as homomers and heteromers [Saul 2013, frontCell Neurosci 7:250]. Purines, such as ATP, have been recognized asimportant neurotransmitters and by acting via their respective receptorsthey have been implicated in various physiological andpathophysiological roles [Burnstock 1993, Drug Dev Res 28:196-206;Burnstock 2011, Prog Neurobiol 95:229-274; Jiang 2012, Cell HealthCytoskeleton 4:83-101].

Among the P2X family members, in particular the P2X3 receptor has beenrecognized as an important mediator of nociception [Burnstock 2013, EurJ Pharmacol 716:24-40; North 2003, J Phyiol 554:301-308; Chizh 2000,Pharmacol Rev 53:553-568]. It is mainly expressed in dorsal root gangliain a subset of nociceptive sensory neurons. During inflammation theexpression of the P2X3 receptor is increased, and activation of P2X3receptor has been described to sensitize peripheral nerves [Fabretti2013, front Cell Neurosci 7:236].

The prominent role of the P2X3 receptor in nociception has beendescribed in various animal models, including mouse and rat models foracute, chronic and inflammatory pain. P2X3 receptor knock-out mice showa reduced pain response [Cockayne 2000, Nature 407:1011-1015; Souslova2000, Nature 407:1015-1017]. P2X3 receptor antagonists have been shownto act anti-nociceptive in different models of pain and inflammatorypain [Ford 2012, Purin Signal 8 (Suppl 1):S3-S26]. The P2X3 receptor hasalso been shown to integrate different nociceptive stimuli. Hyperalgesiainduced by PGE2, ET-1 and dopamine have all been shown to be mediatedvia release of ATP and activation of the P2X3 receptor [Prado 2013,Neuropharm 67:252-258; Joseph 2013, Neurosci 232C: 83-89].

Besides its prominent role in nociception and in pain-related diseasesinvolving both chronic and acute pain, the P2X3 receptor has been shownto be involved in genitourinary, gastrointestinal and respiratoryconditions and disorders, including overactive bladder and chronic cough[Ford 2013, front Cell Neurosci 7:267; Burnstock 2014, Purin Signal10(1):3-50]. ATP-release occurs in these 2 examples from epithelialcells, which in turn activates the P2X3 receptor and induces contractionof bladder and lung muscles respectively leading to premature voiding orcough.

P2X3 subunits do not only form homotrimers but also heterotrimers withP2X2 subunits. P2X3 subunits and P2X2 subunits are also expressed onnerve fibres innervating the tongue, therein taste buds [Kinnamon 2013,front Cell Neurosci 7:264]. In a phyiosological setting, receptorscontaining P2X3 and/or P2X2 subunits are involved in the transmission oftaste from the tongue (bitter, sweet, salty, umami and sour). Recentdata show that while blocking the P2X3 homomeric receptor alone isimportant to achieve anti-nociceptive efficacy, non-selective blockadeof both the P2X3 homomeric receptor and the P2X2/3 heteromeric receptorleads to changes in taste perception which might limit the therapeuticuse of non-selective P2X3 and P2X2/3 receptor antagonists [Ford 2014,purines 2014, abstract book p 15]. Therefore, compounds thatdifferentiate between P2X3 and P2X2/3 receptors are highly desirable.

Compounds blocking both the exclusively P2X3 subunit containing ionchannel (P2X3 homomer) as well as the ion channel composed of P2X2 andP2X3 subunit (P2X2/3 heterotrimer) are called P2X3 and P2X2/3nonselective receptor antagonists [Ford, Pain Manag 2012]. Clinical Philtrials demonstrated that AF-219, a P2X3 antagonist, leads to tastedisturbances in treated subjects by affecting taste sensation via thetongue [e.g. Abdulqawi et al, Lancet 2015; Strand et al, 2015 ACR/ARMPAnnual Meeting, Abstract 2240]. This side effect has been attributed tothe blockade of P2X2/3 channels, i.e. the heterotrimer [A. Ford, London2015 Pain Therapeutics Conference, congress report]. Both P2X2 and P2X3subunits are expressed on sensory nerve fibers innervating the tongue.Knock-out animals deficient for P2X2 and P2X3 subunits show reducedtaste sensation and even taste loss [Finger et al, Science 2005],whereas P2X3 subunit single knock-outs exhibit a mild or no change inphenotype with respect to taste. Moreover, 2 distinct populations ofneurons have been described in the geniculate ganglion expressing eitherP2X2 and P2X3 subunits or P2X3 subunit alone. In an in vivo settingassessing taste preference towards an artificial sweetener via alickometer, only at very high free plasma levels (>100 μM) effects ontaste were observed, indicating that rather the P2X2 and P2X3 subunitsexpressing population plays a major role in taste sensation than theP2X3 subunit expressing population [Vandenbeuch et al, J Physiol. 2015].Hence, as a modified taste perception has profound effects on thequality of life of patients, P2X3-homomeric receptor-selectiveantagonists are deemed to be superior towards non-selective receptorantagonists and are considered to represent a solution towards theproblem of insufficient patient compliance during chronic treatment asindicated by increased drop-out rates during PhII trials [Strand et al,2015 ACR/ARMP Annual Meeting, Abstract 2240 and A. Ford, London 2015Pain Therapeutics Conference, congress report].

Benzamide derivative compounds have been disclosed in prior art for thetreatment or prophylaxis of different diseases:

WO2009/058298 and WO2009/058299 (Merck) disclose novel P2X3 typereceptor antagonists which have a benzamide core structure substitutedwith a phenyl or pyridyl moiety, but not a thiazole, rendering saidcompounds different from the compounds of the present invention.

WO2008/000645 (Roche) addresses P2X3 and/or P2X2/3 receptor antagonistcompounds useful for the treatment of diseases associated with P2Xpurinergic receptors. According to the general formula of claim 1, thebenzamide compounds are substituted with tetrazole. Furthermore, theymay be having substituents like phenyl, pyridinyl, pyrimidinyl,pyridazinyl or thiophenyl. However, there is no thiazolyl substituentdisclosed.

WO2009/077365, WO2009/077366, WO2009/077367 and WO2009/077371 (Roche)disclose a series of benzamide derivatives either substituted withimidazole, triazole, pyrazole or tetrazole which are stated to be usefulfor treatment of diseases associated with P2X purinergic receptors, andmore particularly to P2X3 receptor and/or P2X2/3 receptor antagonists.According to the general formula of claim 1, the benzamide compounds mayhave additional substituents R⁶, R⁷ and R⁸ being C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkyl, halogen atoms or cyano. However, etherssubstituted with the functional groups like —C₂-C₆-alkyl-OR⁴,—(CH₂)_(q)—(C₃-C₇-cycloalkyl), —(CH₂)_(q)-(6- to 12-memberedheterobicycloalkyl), —(CH₂)_(q)-(4- to 7-membered heterocycloalkyl),—(CH₂)_(q)-(5- to 10-membered heteroaryl) or —C₂-C₆-alkynyl are notdisclosed.

US20100152203 (Roche) discloses substituted benzamides with R¹ beingthiadiazolyl and R² being phenyl, pyridinyl, pyrimidinyl, pyridazinyl,or thiophenyl as compounds useful for treatment of diseases associatedwith P2X purinergic receptors, and more particularly relates to P2X3receptor and/or P2X2/3 receptor antagonists usable for treatment ofgenitourinary, pain, inflammatory, gastrointestinal and respiratorydiseases, conditions and disorders. More specifically, the benzamidecompounds may be additionally substituted with C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkyl, halogen atoms or cyano. However, etherssubstituted with the functional groups like —C₂-C₆-alkyl-OR⁴,—(CH₂)_(q)—(C₃-C₇-cycloalkyl), —(CH₂)_(q)-(6- to 12-memberedheterobicycloalkyl), —(CH₂)_(q)-(4- to 7-membered heterocycloalkyl),—(CH₂)_(q)-(5- to 10-membered heteroaryl) or —C₂-C₆-alkynyl are notdisclosed.

US20100324056 (Roche) discloses substituted benzamides with R¹ beingphenyl, thienyl, pyrimidinyl, pyridazinyl, or pyridinyl as compoundsuseful for treatment of diseases associated with P2X purinergicreceptors, and more particularly relates to P2X3 receptor and/or P2X2/3receptor antagonists usable for treatment of genitourinary, pain,inflammatory, gastrointestinal and respiratory diseases, conditions anddisorders. Ethers substituted with the functional groups like—C₂-C₆-alkyl-OR⁴, —(CH₂)_(q)—(C₃-C₇-cycloalkyl), —(CH₂)_(q)-(6- to12-membered heterobicycloalkyl), —(CH₂)_(q)-(4- to 7-memberedheterocycloalkyl), —(CH₂)_(q)-(5- to 10-membered heteroaryl) or—C₂-C₆-alkynyl are not disclosed.

US20100324069 (Genentech) discloses oxazolone- andpyrrolidinone-substituted benzamides and their use for the prophylaxisand/or treatment of diseases which are associated with P2X3 receptorand/or P2X2/3 receptor antagonists. According to the general formula ofclaim 1 the benzamide compounds are additional substituted with apyridine or phenyl. Ether-bearing groups at the benzamide core structureare not disclosed.

WO2006119504 (Renovis) relates to fused heterocyclic compounds of theclass tetrahydronaphthyridines and tetrahydropyrido[4,3-d]pyrimidinesand to pharmaceutical compositions containing such compounds.

WO2008123963 (Renovis) relates to fused heterocyclic compounds of theclass tetrahydropyrido[4,3-d]pyrimidines and pharmaceutical compositionscomprising such compounds. Also provided are methods for preventingand/or treating conditions in mammals, such as (but not limited to)arthritis, Parkinson's disease, Alzheimer's disease, asthma, myocardialinfarction, pain syndromes (acute and chronic or neuropathic),neurodegenerative disorders, schizophrenia, cognitive disorders,anxiety, depression, inflammatory bowel disease and autoimmunedisorders, and promoting neuroprotection, using the fused heterocycliccompounds and pharmaceutical compositions thereof.

WO2008130481 (Renovis) discloses 2-cyanophenyl fused heterocycliccompounds of the class tetrahydropyrido[4,3-d]pyrimidines andpharmaceutical compositions comprising such compounds.

WO2010033168 (Renovis) discloses a series of benzamides substituted withphenyl or pyridyl which are stated to be useful for treatment ofdiseases associated with P2X purinergic receptors, and more particularlyto P2X3 receptor and/or P2X2/3 receptor antagonists. However, benzamideswith additional ether groups are not disclosed.

WO2009110985 (Renovis) relates to phenyl- and pyridyl-substitutedbenzamide compounds and pharmaceutical compositions comprising suchcompounds, but not thiazole-substituted benzamides, rendering saidcompounds different from the compounds of the present invention.

WO2008/055840 (Roche) relates to thiazol- and oxazole-substitutedbenzamides substituted with R² being phenyl, pyridinyl, pyrimidinyl,pyridazinyl or thiophenyl that can be used for treating diseasesassociated with P2X purinergic receptors, and more particularly as P2X3and/or P2X2/3 receptor antagonists. However, the thiazole substitutedbenzamides have in fact C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl,halo-C₁-C₆-alkoxy groups, halogen atoms or cyano, but ethers substitutedwith the functional groups like —C₂-C₆-alkyl-OR⁴,—(CH₂)_(q)—(C₃-C₇-cycloalkyl), —(CH₂)_(q)-(6- to 12-memberedheterobicycloalkyl), —(CH₂)_(q)-(4- to 7-membered heterocycloalkyl),—(CH₂)_(q)-(5- to 10-membered heteroaryl) or —C₂-C₆-alkynyl are notdisclosed.

So, the state of the art described above does not describe the specificthiazole substituted benzamide compounds of general formula (I) of thepresent invention as defined herein or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or a salt thereof, or amixture of same, as described and defined herein, and as hereinafterreferred to as “compounds of the present invention”, or theirpharmacological activity.

It has now been found, and this constitutes the basis of the presentinvention, that said compounds of the present invention have surprisingand advantageous properties.

In particular, said compounds of the present invention have surprisinglybeen found to effectively inhibit the P2X3 receptor and may therefore beused for the treatment or prophylaxis of following diseases:

-   -   genitourinary, gastrointestinal, respiratory and pain-related        diseases, conditions and disorders;    -   gynecological diseases including dysmenorrhea (primary and        secondary dysmenorrhea), dyspareunia, endometriosis, and        adenomyosis; endometriosis-associated pain;        endometriosis-associated symptoms, wherein said symptoms are in        particular dysmenorrhea, dyspareunia, dysuria, or dyschezia;        endometriosis-associated proliferation; pelvic hypersensitivity;    -   urinary tract disease states associated with the bladder outlet        obstruction; urinary incontinence conditions such as reduced        bladder capacity, increased frequency of micturition, urge        incontinence, stress incontinence, or bladder hyperreactivity;        benign prostatic hypertrophy; prostatic hyperplasia;        prostatitis; detrusor hyperreflexia; overactive bladder and        symptoms related to overactive bladder wherein said symptoms are        in particular increased urinary frequency, nocturia, urinary        urgency or urge incontinence; pelvic hypersensitivity;        urethritis; prostatitis; prostatodynia; cystitis, in particular        Interstitial cystitis; idiopathic bladder hypersensitivity [Ford        2014, purines 2014, abstract book p 15];    -   pain syndromes (including acute, chronic, inflammatory and        neuropathic pain), preferably inflammatory pain, low back pain        surgical pain, visceral pain, dental pain, periodontitis,        premenstrual pain, endometriosis-associated pain, pain        associated with fibrotic diseases, central pain, pain due to        burning mouth syndrome, pain due to burns, pain due to migraine,        cluster headaches, pain due to nerve injury, pain due to        neuritis, neuralgias, pain due to poisoning, pain due to        ischemic injury, pain due to interstitial cystitis, cancer pain,        pain due to viral, parasitic or bacterial infections, pain due        to traumatic nerve-injury, pain due to post-traumatic injuries        (including fractures and sport injuries), pain due to trigeminal        neuralgia, pain associated with small fiber neuropathy, pain        associated with diabetic neuropathy, postherpetic neuralgia,        chronic lower back pain, neck pain phantom limb pain, pelvic        pain syndrome, chronic pelvic pain, neuroma pain, complex        regional pain syndrome, pain associated with gastrointestinal        distension, chronic arthritic pain and related neuralgias, and        pain associated with cancer, Morphine-resistant pain, pain        associated with chemotherapy, HIV and HIV treatment-induced        neuropathy; and pain associated with diseases or disorders        selected from the group consisting of hyperalgesia, allodynia,        functional bowel disorders (such as irritable bowel syndrome)        and arthritis (such as osteoarthritis, rheumatoid arthritis and        ankylosing spondylitis);    -   Epilepsy, partial and generalized seizures;    -   Respiratory disorders including chronic obstructive pulmonary        disorder (COPD) [Ford 2013, European Respiratory Society Annual        Congress 2013], asthma [Ford 2014, 8th Pain        Migraine Therapeutics Summit], bronchospasm, pulmonary fibrosis,        acute cough, chronic cough including chronic idiopathic and        chronic refractory cough;    -   Gastrointestinal disorders including irritable bowel syndrome        (IBS), inflammatory bowel disease (IBD), biliary colic and other        biliary disorders, renal colic, diarrhea-dominant IBS,        gastroesophageal reflux, gastrointestinal distension, Crohn's        disease and the like;    -   neurodegenerative disorders such as Alzheimer's disease,        Multiple Sclerosis, Parkinson's disease, Brain ischemia and        traumatic brain injury;    -   myocardial infarction, lipid disorders;    -   pain-associated diseases or disorders selected from the group        consisting of hyperalgesia, allodynia, functional bowel        disorders (such as irritable bowel syndrome), gout, arthritis        (such as osteoarthritis [Ford 2014, 8^(th) Pain        Migraine Therapeutics Summit], rheumatoid arthritis and        ankylosing spondylitis), burning mouth syndrome, burns, migraine        or cluster headaches, nerve injury, traumatic nerve injury,        post-traumatic injuries (including fractures and sport        injuries), neuritis, neuralgias, poisoning, ischemic injury,        interstitial cystitis, cancer, trigeminal neuralgia, small fiber        neuropathy, diabetic neuropathy, chronic arthritis and related        neuralgias, HIV and HIV treatment-induced neuropathy, pruritus;        impaired wound healing and disease of the skeleton like        degeneration of the joints    -   pruritus.

The compounds of the present invention show high P2X3 receptorinhibition and furthermore selectivity over the P2X2/3 receptor.Selective inhibition of the P2X3 receptor over the P2X2/3 receptor meansat least 3-fold selectivity over the P2X2/3 receptor. Preferredcompounds of the present invention show at least 10-fold selectivityover the P2X2/3 receptor. In addition to that, more preferred compoundsof the present invention show further advantageous properties that arebeneficial for their use as medicaments, such as desirablepharmacokinetic profiles that provide suitable metabolic stability andoral bioavailability. In addition to that, even more preferred compoundsof the present invention show further advantageous properties that arebeneficial for their use as medicaments, such as desirablepharmacokinetic profiles that provide suitable metabolic stability andoral bioavailability, and at least one additional advantageous propertychosen from an advantageous cardiovascular profile and a suitable CYPinhibition profile.

SUMMARY OF THE INVENTION

The present invention covers compounds of general formula (I):

in which

-   R¹ represents a halogen atom, C₁-C₄-alkyl or C₃-C₆-cycloalkyl,    wherein C₁-C₄-alkyl is optionally substituted with 1-5 halogen atoms    which are the same or different;-   R² represents —C₂-C₆-alkyl-OR⁴, —(CH₂)_(q)—(C₃-C₇-cycloalkyl),    —(CH₂)_(q)-(6- to 12-membered heterobicycloalkyl), —(CH₂)_(q)-(4- to    7-membered heterocycloalkyl), —(CH₂)_(q)-(5- to 10-membered    heteroaryl) or —C₂-C₆-alkynyl; and    -   wherein said —(CH₂)_(q)—(C₃-C₇-cycloalkyl), —(CH₂)_(q)-(6- to        12-membered heterobicycloalkyl) and —(CH₂)_(q)-(4- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents which are the same or different, at any ring carbon        atom and selected from the group consisting of    -   C₁-C₄ alkyl, optionally substituted with 1-5 halogen atoms which        are the same or different, a halogen atom, —NR^(a)R^(b), COOR⁵        and oxo (═O); and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(6- to 12-membered heterobicycloalkyl) and        —(CH₂)_(q)-(4- to 7-membered heterocycloalkyl) is substituted        with R^(c); and    -   wherein said —(CH₂)_(q)-(5- to 10-membered heteroaryl) is        optionally substituted with one or more substituents which are        the same or different, and selected from the group consisting of        C₁-C₄-alkyl, optionally substituted with 1-5 halogen atoms which        are the same or different, a halogen atom, —NR^(a)R^(b) and        —COOR⁵;-   R³ represents hydrogen or C₁-C₄-alkyl, which is optionally    substituted with 1-5 halogen atoms which are the same or different;-   R⁴ and R⁵ represent hydrogen or C₁-C₄-alkyl;-   R^(a) and R^(b) represent hydrogen or C₁-C₄-alkyl;-   R^(c) represents hydrogen, C₁-C₄-alkyl, optionally substituted with    1-5 halogen atoms which are the same or different,    —C(O)O—C₁-C₄-alkyl, or —C(O)—C₁-C₄-alkyl;-   A represents 5- to 10-membered heteroaryl which is optionally    substituted with one or more substituents, which are the same or    different, and selected from the group consisting of a halogen atom,    C₁-C₃-alkyl, and C₁-C₃-alkoxy, wherein C₁-C₃-alkyl and C₁-C₃-alkoxy    are optionally substituted with 1-5 halogen atoms which are the same    or different;-   q represents an integer of 0, 1, or 2;    or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

The present invention further relates to compounds of general formula(Ia),

-   in which A, R¹, R² and R³ have the meanings as defined in formula    (I), preferably R³ represents C₁-C₄-alkyl, more preferably methyl;-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

The present invention further relates to pharmaceutical compositions andcombinations comprising said compounds, to use of said compounds formanufacturing a medicament for the treatment or prophylaxis of diseasesor disorders and for the treatment of pains which are associated withsuch diseases.

DETAILED DESCRIPTION OF THE INVENTION

The terms as mentioned in the present text have preferably the followingmeanings:

The term “halogen atom”, “halo-” or “Hal-” is to be understood asmeaning a fluorine, chlorine, bromine or iodine atom, preferably afluorine or a chlorine atom.

The term “alkyl” is to be understood as meaning a linear or branched,saturated, monovalent hydrocarbon group with the number of carbon atomsas specified and having as a rule, 2 to 6 in case of R², and 1 to 4 forall other alkyl substituents, preferably 1 to 3, carbon atoms, by way ofexample and by preference a methyl, ethyl, propyl, butyl, pentyl, hexyl,iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl,1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl,1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl,2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl,1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or an isomer thereof.Particularly, said group has 1, 2, 3 or 4 carbon atoms (“C₁-C₄-alkyl”),e.g. a methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl,sec-butyl, tert-butyl group, more particularly 1, 2 or 3 carbon atoms(“C₁-C₃-alkyl”), e.g. a methyl, ethyl, n-propyl- or iso-propyl group,and even more particularly 1 or 2 carbon atoms (“C₁-C₂-alkyl”), e.g. amethyl or ethyl group.

The term “C₁-C₄-alkyl, optionally substituted with 1-5 halogen atoms”,or in analogy “C₁-C₃-alkyl, optionally substituted with 1-5 halogenatoms” or “C₁-C₂-alkyl which are optionally substituted with 1-5 halogenatoms”, is to be understood as meaning a linear or branched, saturated,monovalent hydrocarbon group in which the term “C₁-C₄-alkyl”,“C₁-C₃-alkyl” or “C₁-C₂-alkyl” is defined supra, and in which one ormore hydrogen atoms is replaced by a halogen atom, which are the same ordifferent, i.e. one halogen atom being independent from another. Inparticular, halogen is fluorine or chlorine.

The term “C₁-C₄-alkyl, optionally substituted with 1-5 fluorine atoms”,or in analogy “C₁-C₃-alkyl, optionally substituted with 1-5 fluorineatoms” or “C₁-C₂-alkyl, optionally substituted with 1-5 fluorine atoms”,is to be understood as meaning a linear or branched, saturated,monovalent hydrocarbon group in which the term “C₁-C₄-alkyl”,“C₁-C₃-alkyl” or “C₁-C₂-alkyl” is defined supra, and in which one ormore hydrogen atoms is replaced by a fluorine atom.

Said “C₁-C₄-alkyl, optionally substituted with 1-5 fluorine atoms” or“C₁-C₄-alkyl group, optionally substituted with 1-5 halogen atoms” is,for example, —CH₂CH₂CH₂CF₃.

Similarly, the above-mentioned applies to “C₁-C₃-alkyl, optionallysubstituted with 1-5 halogen atoms”, or “C₁-C₂-alkyl, optionallysubstituted with 1-5 halogen atoms”, or “C₁-C₃-alkyl, optionallysubstituted with 1-5 fluorine atoms”, or “C₁-C₂-alkyl, optionallysubstituted with 1-5 fluorine atoms”. Thus said “C₁-C₃-alkyl optionallysubstituted with 1-5 halogen atoms” or “C₁-C₃-alkyl optionallysubstituted with 1-5 fluorine atoms” is, for example, —CH₂CH₂CF₃.

Said “C₁-C₂-alkyl optionally substituted with 1-5 halogen atoms” or“C₁-C₂-alkyl optionally substituted with 1-5 fluorine atoms” is, forexample, —CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CH₂CHF₂, or —CH₂CF₃.

Under the proviso, that R² in formula (I) or (la) is —C₂-C₆-alkyl-OR⁴,“C₂-C₆-alkyl” is to be understood as C₁-C₅-alkylene which is bound tothe phenolic oxygen via —CH₂— group. For example C₁-C₅-alkylene ismethylene, ethylene, propylene, butylene, pentylene, iso-propylene,iso-butylene, sec-butylene, tert-butylene, iso-pentylene,2-methylbutylene, 1-methylbutylene, 1-ethylpropylene,1,2-dimethylpropylene, neo-pentylene, 1,1-dimethylpropylene.

Under the proviso, that R² in formula (I) or (Ia) is —C₂-C₆-alkyl-OR⁴,“C₂-C₆-alkyl” is also to be understood as C₁-C₄-alkylene which is boundto the phenolic oxygen via —CH—CH₃ group.

Under the proviso, that R² in formula (I) or (Ia) is —C₂-C₄-alkyl-OR⁴,“C₂-C₄-alkyl” is to be understood as C₁-C₃-alkylene which is bound tothe phenolic oxygen via —CH₂— group. Under the proviso that R² informula (I) or (Ia) is —C₂-C₄-alkyl-OR⁴, “C₂-C₄-alkyl” is also to beunderstood as C₁-C₂-alkylene which is bound to the phenolic oxygen via—CH—CH₃ group.

Under the proviso, that R² in formula (I) or (Ia) is —C₂-C₄-alkyl-OH,“C₂-C₄-alkyl” is to be understood as C₁-C₃-alkylene which is bound tothe phenolic oxygen via —CH₂— group. Under the proviso that R² informula (I) or (Ia) is —C₂-C₄-alkyl-OH, “C₂-C₄-alkyl” is also to beunderstood as C₁-C₂-alkylene which is bound to the phenolic oxygen via—CH—CH₃ group.

Under the proviso, that R² in formula (I) or (Ia) is —C₂-C₆-alkyl-OR⁴,“—OR⁴” is either at a tertiary, secondary or primary carbon atom of the—C₂-C₆-alkyl chain.

Under the proviso, that R² in formula (I) or (Ia) is —C₂-C₄-alkyl-OR⁴,“—OR⁴” is either at a tertiary, secondary or primary carbon atom of the—C₂-C₄-alkyl chain. Under the proviso, that R² in formula (I) or (Ia) is—C₂-C₄-alkyl-OH, “—OH” is either at a tertiary, secondary or primarycarbon atom of the —C₂-C₄-alkyl chain.

For example, said —C₂-C₆-alkyl-OR⁴ is 3-hydroxybutan-2-yl,(2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl,(2R,3S)-3-hydroxybutan-2-yl, (2S,3R)-3-hydroxybutan-2-yl,(2R,3R)-3-methoxybutan-2-yl, (2S,3S)-3-methoxybutan-2-yl,(2R,3S)-3-methoxybutan-2-yl, (2S,3R)-3-methoxybutan-2-yl,3-methoxybutan-2-yl, 2-hydroxy-2-methylpropan-1-yl,2-methoxy-2-methylpropan-1-yl, 3-hydroxypropan1-yl, 3-hydroxybutan-1-yl,3-hydroxy-3-methylbutan-1-yl, 3-hydroxy-2-methylbutan-1-yl,3-hydroxy-2,2-dimethylpropan-1-yl, 4-hydroxy-3-methylbutan-2-yl,4-hydroxy-3-methylpent-1-yl, 4-hydroxy-4-methylpent-1-yl,2-hydroxy-2-methylpropan-1-yl, 2-methoxy-2-methyl-propan-1-yl,2-methoxyethan-1-yl, 3-methoxypropan-1-yl, 4-methoxybutan-1-yl,2-ethoxyethan-1-yl, 3-ethoxypropan-1-yl, 4-ethoxybutan-1-yl,2-iso-propoxyethan-1-yl, 3-iso-propoxypropan-1-yl,4-iso-propoxybutan-1-yl, 2-hydroxyethan-1-yl, 3-hydroxy-propan-1-yl,4-hydroxybutan-1-yl, preferably 3-hydroxybutan-2-yl,(2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl,(2R,3S)-3-hydroxybutan-2-yl, (2S,3R)-3-hydroxybutan-2-yl, morepreferably (2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl.

For example, said —C₂-C₄-alkyl-OR⁴ or —C₂-C₄-alkyl-OH is preferably3-hydroxybutan-2-yl, (2R,3R)-3-hydroxybutan-2-yl,(2S,3S)-3-hydroxybutan-2-yl, (2R,3S)-3-hydroxybutan-2-yl,(2S,3R)-3-hydroxybutan-2-yl, more preferably(2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl.

The term “alkoxy” is to be understood as meaning a linear or branched,saturated, monovalent, hydrocarbon group of formula —O-alkyl, in whichthe term “alkyl” is defined as meaning a linear or branched, saturated,monovalent hydrocarbon group with the number of carbon atoms asspecified and having as a rule, 1 to 3, preferably 1 to 2 alkylsubstituents, especially preferably 1, carbon atoms. Particularly, saidgroup has 1, 2 or 3 carbon atoms (“C₁-C₃-alkoxy”), e.g. a methoxy,ethoxy, n-propoxy or iso-propoxy group, and even more particularly 1 or2 carbon atoms (“C₁-C₂-alkoxy”), e.g. a methoxy or ethoxy group.

The term “C₁-C₃-alkoxy optionally substituted with 1-5 halogen atoms” isto be understood as meaning a linear or branched, saturated, monovalenthydrocarbon group in which the term “C₁-C₃-alkoxy” is defined supra, andin which one or more hydrogen atoms is replaced by a halogen atom, whichare the same or different, i.e. one halogen atom being independent fromanother. In particular, halogen is fluorine or chlorine.

Said “C₁-C₃-alkoxy” group is optionally substituted with 1 to 5 fluorineatoms, for example, —OCF₃, —OCHF₂, —OCH₂F, —OCF₂CF₃, —OCH₂CHF₂,—OCH₂CF₃, —OCH₂CH₂CF₃, or —OCH₂CF₂CF₃. In particular, said“C₁-C₃-alkoxy” group optionally substituted with fluorine is —OCF₃.

The term “C₂-C₆-alkynyl” is to be understood as meaning a linear orbranched, monovalent hydrocarbon group which contains one or more triplebonds, preferably one triple bond, and which contains 2, 3, 4, 5 or 6carbon atoms, particularly 3 or 4 carbon atoms (“C₃-C₄-alkynyl”). SaidC₂-C₆-alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl,but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl,pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl,hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl,1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl,1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl,1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl,4-methylpent2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl,3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl,1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl,2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl,or 3,3-dimethylbut-1-ynyl group. Particularly, said alkynyl group isprop-1-ynyl or prop-2-ynyl.

The term “cycloalkyl” is to be understood as meaning a saturated,monovalent, monocyclic hydrocarbon ring with the number of carbon atomsas specified and having as a rule, 3 to 7 or 3 to 6 ring carbon atoms,preferably 3 to 4 ring carbon atoms.

“C₃-C₇-cycloalkyl” is to be understood as meaning a saturated,monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7carbon atoms. Said C₃-C₇-cycloalkyl group is for example a cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring. Each hydrogenof a cycloalkyl carbon may be replaced by a substituent as furtherspecified. Particularly, said ring contains 3, 4, 5 or 6 carbon atoms(“C₃-C₆-cycloalkyl”), preferably 3 or 4 carbon atoms(“C₃-C₄-cycloalkyl”).

In case of R² in formula (I) or (Ia), said “C₃-C₇-cycloalkyl” in“(CH₂)_(q)—(C₃-C₇-cycloalkyl)” is, unless indicated otherwise,optionally substituted with one or more substituents which are the sameor different, at any ring carbon atom and selected from the groupconsisting of C₁-C₄ alkyl, optionally substituted with 1-5 halogen atomswhich are the same or different, a halogen atom, —NR^(a)R^(b), COOR⁵ andoxo (═O). In case of R² in formula (I) or (Ia), said “C₃-C₄-cycloalkyl”as such or “C₃-C₄-cycloalkyl” in “CH₂—(C₃-C₄-cycloalkyl)” is, unlessindicated otherwise, optionally substituted with one or moresubstituents which are the same or different, at any ring carbon atomand selected from a group consisting of C₁-C₄-alkyl, optionallysubstituted with 1-5 halogen atoms which are the same or different, ahalogen atom, —NR^(a)R^(b), —COOR⁵ and oxo (═O).

The term “heterocycloalkyl” is to be understood as meaning a saturated,monovalent, monocyclic hydrocarbon ring with the number of ring atoms asspecified in which one, two or three ring atoms of the hydrocarbon ringis/are replaced by one, two or three heteroatoms orheteroatom-containing groups independently selected from O, S, S(═O),S(═O)₂, or N.

“4- to 7-membered heterocycloalkyl” is to be understood as meaning asaturated, monovalent, monocyclic “heterocycloalkyl” ring as definedsupra which contains 4, 5, 6 or 7 ring atoms.

Similarly, “4- to 6-membered heterocycloalkyl” is to be understood asmeaning a saturated, monovalent, monocyclic “heterocycloalkyl” ring asdefined supra which contains 4, 5 or 6 ring atoms.

In case of R² in formula (I) or (Ia), said 4- to 7-memberedheterocycloalkyl or 4- to 6-membered heterocycloalkyl is, unlessindicated otherwise, optionally substituted with one or moresubstituents which are the same or different, at any ring carbon atomand selected from the group consisting of C₁-C₄ alkyl, optionallysubstituted with 1-5 halogen atoms which are the same or different, ahalogen atom, —NR^(a)R^(b), COOR⁵ and oxo (═O); and whereinindependently any ring nitrogen atom, if present in said 4- to7-membered or 4- to 6-membered heterocycloalkyl is substituted withR^(c); it being possible for said 4- to 7-membered or 4- to 6-memberedheterocycloalkyl group to be attached to the rest of the molecule viaany one of the carbon atoms or, if present, a nitrogen atom.Accordingly, any ring nitrogen atom if present in said 4- to 7-memberedor 4- to 6-membered heterocycloalkyl group is only substituted withR^(c), if the designated atom's normal valency under the existingcircumstances is not exceeded.

Particularly, said 4- to 7-membered heterocycloalkyl can contain 3, 4, 5or 6 carbon atoms, and one or two of the above-mentioned heteroatoms orheteroatom-containing groups provided that the total number of ringatoms is not greater than 7, more particularly said heterocycloalkyl cancontain 3, 4 or 5 carbon atoms, and one or two of the above-mentionedheteroatoms or heteroatom-containing groups provided that the totalnumber of ring atoms is not greater than 6 (a “4- to 6-memberedheterocycloalkyl”).

Particularly, without being limited thereto, said heterocycloalkyl canbe a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-memberedring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, or a 6-membered ring, such astetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, or a 7-membered ring, such as a diazepanyl ring, forexample.

Particularly, without being limited thereto, said heterocycloalkyl canbe in a more preferred embodiment (3R)-tetrahydrofuran-3-yl,(3S)-tetrahydrofuran-3-yl, 4-methylmorpholin-2-yl,(2R)-4-methylmorpholin-2-yl, (2S)-4-methylmorpholin-2-yl,4-methylmorpholin-3-yl, (3R)-4-methylmorpholin-3-yl, or(3S)-4-methylmorpholin-3-yl, most preferred (2R)-4-methylmorpholin-2-yl.

The term “6- to 12-membered heterobicycloalkyl” is to be understood asmeaning a saturated, monovalent bicyclic hydrocarbon radical in whichthe two rings share one or two common ring atoms, and wherein saidbicyclic hydrocarbon radical contains 5, 6, 7, 8, 9 or 10 carbon atomsand one, two or three heteroatoms or heteroatom-containing groupsindependently selected from O, S, S(═O), S(═O)₂, or N, provided that thetotal number of ring atoms is not greater than 12. Said 6- to12-membered heterobicycloalkyl is, unless indicated otherwise,optionally substituted with one or more substituents, which are the sameor different, at any ring carbon atom and selected from the groupconsisting of C₁-C₄ alkyl, optionally substituted with 1-5 halogen atomswhich are the same or different, a halogen atom, —NR^(a)R^(b), COOR⁵ andoxo (═O); and wherein independently any ring nitrogen atom, if presentin said 6- to 12-membered heterobicycloalkyl is substituted with R^(c);it being possible for said 6- to 12-membered heterobicycloalkyl to beattached to the rest of the molecule via any one of the carbon atoms or,if present, a nitrogen atom. Accordingly, any ring nitrogen atom ifpresent in said 6- to 12-membered heterobicycloalkyl is only substitutedwith R^(c), if the designated atom's normal valency under the existingcircumstances is not exceeded. Said 6- to 12-membered heterobicycoalkylis, for example, azabicyclo[3.3.0]octyl, azabicyclo-[4.3.0]nonyl,diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl,thiazabicyclo[4.3.0]nonyl or azabicyclo[4.4.0]decyl.

Heterospirocycloalkyl and bridged heterocycloalkyl, as defined below,are also included within the scope of this definition.

The term “heterospirocycloalkyl” is to be understood as meaning asaturated, monovalent bicyclic hydrocarbon radical in which the tworings share one common ring atom, and wherein said bicyclic hydrocarbonradical contains 5, 6, 7, 8, 9 or 10 carbon atoms, and one, two or threeheteroatoms or heteroatom-containing groups independently selected fromO, S, S(═O), S(═O)₂, or N, provided that the total number of ring atomsis not greater than 12. It is possible for said heterospirocycloalkyl tobe attached to the rest of the molecule via any one of the carbon atomsor, if present, a nitrogen atom. Said heterospirocycloalkyl is, forexample, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl,oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl,oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, oxazaspiro[5.5]undecyl,diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, orazaspiro[5.5]decyl.

The term “bridged heterocycloalkyl” is to be understood as meaning asaturated, monovalent bicyclic hydrocarbon radical in which the tworings share two common ring atoms which are not immediately adjacent,and wherein said bicyclic hydrocarbon radical contains 5, 6, 7, 8, 9 or10 carbon atoms, and one, two or three heteroatoms orheteroatom-containing groups independently selected from O, S, S(═O),S(═O)₂, or N, provided that the total number of ring atoms is notgreater than 12. It is possible for said bridged heterocycloalkyl to beattached to the rest of the molecule via any one of the carbon atoms or,if present, a nitrogen atom. Said bridged heterocycloalkyl is, forexample, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl,thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl,azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl,oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl,azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl,oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl,azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]-nonyl,oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1]nonyl,azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl,oxazabicyclo[4.2.1]nonyl, thiazabicyclo[4.2.1]nonyl,azabicyclo[3.3.2]decyl, diazabicyclo[3.3.2]decyl,oxazabicyclo[3.3.2]decyl, thiazabicyclo[3.3.2]decyl, orazabicyclo[4.2.2]decyl.

The term “heteroaryl” is understood as meaning a monovalent, monocyclicor bicyclic hydrocarbon ring system with at least one aromatic ring withthe number of ring system atoms as specified and wherein one, two orthree ring atoms of the monovalent, monocyclic or bicyclic hydrocarbonring system is/are replaced by one, two or three heteroatoms orheteroatom-containing groups independently selected from O, S, S(═O),S(═O)₂, or N.

“5- to 10-membered heteroaryl” is understood as meaning a heteroarylhaving 5, 6, 7, 8, 9 or 10 ring atoms (a “5- to 10-membered heteroaryl”)and wherein one, two or three ring atoms of the monovalent, monocyclicor bicyclic hydrocarbon ring system is/are replaced by one, two or threeheteroatoms or heteroatom-containing groups independently selected fromO, S, S(═O), S(═O)₂, or N. Particularly, heteroaryl is selected fromthienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,thia-4H-pyrazolyl etc. and benzo derivatives thereof, such as, forexample, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl,benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; orpyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., andbenzo derivatives thereof, such as, for example, quinolinyl,quinazolinyl, isoquinolinyl, etc.; indolizinyl, and benzo derivativesthereof; or cimolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, etc. Incase of R² of formula (I) or (Ia), said 5- to 10-membered heteroaryl is,unless indicated otherwise, optionally substituted with one or moresubstituents which are the same or different, and selected from thegroup consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogenatoms which are the same or different, a halogen atom, —NR^(a)R^(b) and—COOR⁵.

In case of R² of formula (I) or (Ia), said 5- to 10-membered heteroaryloptionally substituted as described above, can be in particularsubstituted with C₁-C₂-alkyl at any ring N, if present.

In case of A of formula (I) or (Ia), said 5- to 10-membered heteroarylis, unless indicated otherwise, optionally substituted with one or moresubstituents, which are the same or different, and selected from thegroup consisting of a halogen atom, C₁-C₃-alkyl, and C₁-C₃-alkoxy,wherein C₁-C₃-alkyl and C₁-C₃-alkoxy are optionally substituted with 1-5halogen atoms which are the same or different.

In case of A of formula (I) or (Ia), a “5- or 6-membered heteroaryl” isunderstood as meaning a heteroaryl having 5 or 6 ring atoms and whereinone, two or three ring atoms of the hydrocarbon ring system is/arereplaced by one, two or three heteroatoms or heteroatom-containinggroups independently selected from 0, S, S(═O), S(═O)₂, or N. Said “5-or 6-membered heteroaryl” is, unless indicated otherwise, optionallysubstituted with one or more substituents, which are the same ordifferent, and selected from the group consisting of a halogen atom,C₁-C₃-alkyl, and C₁-C₃-alkoxy, wherein C₁-C₃-alkyl and C₁-C₃ alkoxy areoptionally substituted with 1-5 halogen atoms which are the same ordifferent

A 5-membered heteroaryl group is preferably selected from thienyl,furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,thia-4H-pyrazolyl.

A 6-membered heteroaryl group is preferably selected from pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.

In particular, said 5- or 6-membered heteroaryl is, optionallysubstituted with preferably one or two substituents, which are the sameor different, and selected from a fluorine or chlorine atom,C₁-C₂-alkyl, optionally substituted with 1-5 fluorine atoms, orC₁-C₂-alkoxy, optionally substituted with 1-5 fluorine atoms.

In particular, said 5- or 6-membered heteroaryl is a 6-memberedheteroaryl with one or two nitrogen atom(s) and is optionallysubstituted with one or two substituents, which are the same ordifferent, and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,optionally substituted with 1-5 fluorine atoms.

Preferably said 6-membered heteroaryl is CF₃-pyrimidinyl, mostpreferably 2-CF₃-pyrimidin-5-yl. Also preferred is CF₃-pyridazinyl, mostpreferably 6-CF₃-pyridazin-3-yl.

In general, and unless otherwise mentioned, the term “heteroaryl”includes all possible isomeric forms thereof, e.g. the positionalisomers thereof. Thus, for some illustrative non-restricting example,the term pyridyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl;or the term pyrimidinyl includes pyrimidin-2-yl, pyrimidin-4-yl andpyrimidin-5-yl; or the term pyridazinyl includes pyridazin-3-yl andpyridazin-4-yl; or the term thiazolyl includes 1,3-thiazol-5-yl,1,3-thiazol-4-yl and 1,3-thiazol-2-yl.

The term “C₁-C₄” as used throughout this text is to be understood asmeaning a group having a finite number of carbon atoms of 1 to 4, i.e.1, 2, 3 or 4 carbon atoms, e.g. in the context of the definition of“C₁-C₄-alkyl”, it is to be understood as meaning an alkyl group having afinite number of carbon atoms of 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms.

The term “C₂-C₆” as used throughout this text is to be understood asmeaning a group having a finite number of carbon atoms of 2 to 6, i.e.2, 3, 4, 5 or 6 carbon atoms, e.g. in the context of the definition of“C₂-C₆-alkyl”, it is to be understood as meaning an alkyl group having afinite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5 or 6 carbonatoms. It is to be understood further that said term “C₂-C₆” is to beinterpreted as any sub-range comprised therein, e.g. C₂-C₆, C₃-C₅,C₃-C₄, C₂-C₃, C₂-C₄, C₂-C₅; particularly C₂-C₃.

The term “C₁-C₃” as used in the context of the definition “C₁-C₃-alkoxy”is to be understood as meaning an alkoxy group, having a finite numberof carbon atoms of 1 to 3, i.e. 1, 2 or 3 carbon atoms.

The same applies to other mentioned “alkyl”, alkynyl or “alkoxy” asmentioned herein and as it is to be understood by a skilled person.

It is to be understood further that for example a term “C₁-C₆” is to beinterpreted as any sub-range comprised therein, e.g. C₁-C₆, C₂-C₃,C₂-C₆, C₃-C₄, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅; particularly C₁-C₂, C₁-C₃,C₁-C₄, C₁-C₅, C₁-C₆; more particularly C₁-C₄.

Similarly, the mentioned above applies to “C₁-C₄-alkyl”, “C₁-C₃-alkyl”,“C₁-C₃-alkoxy”, “C₁-C₂-alkyl” or “C₁-C₂-alkoxy” optionally substitutedwith 1-5 halogen which are the same or different.

Similarly, as used herein, the term “C₂-C₆”, as used throughout thistext, e.g. in the context of the definitions of “C₂-C₆-alkynyl”, is tobe understood as meaning an alkynyl group having a finite number ofcarbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to beunderstood further that said term “C₂-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₂-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄,C₂-C₅; particularly C₂-C₃ and C₂-C₄.

Further, as used herein, the term “C₃-C₇”, as used throughout this text,is to be understood as meaning a group having a finite number of carbonatoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms, e.g. in the contextof the definition of “C₃-C₇-cycloalkyl”, it is to be understood asmeaning a cycloalkyl group having a finite number of carbon atoms of 3to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms. It is to be understood furtherthat said term “C₃-C₇” is to be interpreted as any sub-range comprisedtherein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆, C₅-C₇; particularlyC₃-C₆.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “optionally substituted” means that the number of substituentscan be zero. Unless otherwise indicated, optionally substituted groupsmay be substituted with as many optional substituents as can beaccommodated by replacing a hydrogen atom with a non-hydrogensubstituent on any available carbon or nitrogen atom. Commonly, thenumber of optional substituents (when present) ranges from 1 to 5, inparticular from 1 to 3.

As used herein, the term “one or more”, e.g. in the definition of thesubstituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or five,particularly one, two, three or four, more particularly one, two orthree, even more particularly one or two”.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, sulphur,fluorine and chlorine such as ²H (deuterium), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F and ³⁶Cl, respectively.Certain isotopic variations of a compound of the invention, for example,those in which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

Optical isomers can be obtained by resolution of the racemic mixturesaccording to conventional processes, for example, by the formation ofdiastereoisomeric salts using an optically active acid or base orformation of covalent diastereomers. Examples of appropriate acids aretartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.Mixtures of diastereoisomers can be separated into their individualdiastereomers on the basis of their physical and/or chemical differencesby methods known in the art, for example, by chromatography orfractional crystallisation. The optically active bases or acids are thenliberated from the separated diastereomeric salts. A different processfor separation of optical isomers involves the use of chiralchromatography (e.g., chiral HPLC columns), with or without conventionalderivatisation, optimally chosen to maximise the separation of theenantiomers. Suitable chiral HPLC columns are manufactured by Daicel,e.g., Chiracel OD and Chiracel OJ among many others, all routinelyselectable. Enzymatic separations, with or without derivatisation, arealso useful. The optically active compounds of this invention canlikewise be obtained by chiral syntheses utilizing optically activestarting materials.

In order to limit different types of isomers from each other referenceis made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

Further, the compounds of the present invention may exist as tautomers.

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, andco-precipitates.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example asstructural element of the crystal lattice of the compounds. The amountof polar solvents, in particular water, may exist in a stoichiometric ornon-stoichiometric ratio. In the case of stoichiometric solvates, e.g. ahydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc.solvates or hydrates, respectively, are possible. The present inventionincludes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any pharmaceutically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

The term “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19. A suitable pharmaceuticallyacceptable salt of the compounds of the present invention may be, forexample, an acid-addition salt of a compound of the present inventionbearing a nitrogen atom, in a chain or in a ring, for example, which issufficiently basic, such as an acid-addition salt with an inorganicacid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric,bisulfuric, phosphoric, or nitric acid, for example, or with an organicacid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic,propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic,salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically acceptablecation, for example a salt with N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groupsmay be quaternised with such agents as lower alkyl halides such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides and others.

Those skilled in the art will further recognise that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

Unless otherwise indicated, the compounds of the present invention arealso referred to isomers, enantiomers, diastereomers, racemates,hydrates, solvates, or a salt thereof, or a mixture of same.

As used herein, the term “in vivo hydrolysable ester” is understood asmeaning an in vivo hydrolysable ester of a compound of the presentinvention containing a carboxy or hydroxy group, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include for examplealkyl, cycloalkyl and optionally substituted phenylalkyl, in particularbenzyl esters, C₁-C₆ alkoxymethyl esters, e.g. methoxymethyl, C₁-C₆alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters,C₃-C₈ cycloalkoxy-carbonyloxy-C₁-C₆ alkyl esters, e.g.1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g.5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆-alkoxycarbonyloxyethylesters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxygroup in the compounds of this invention. An in vivo hydrolysable esterof a compound of the present invention containing a hydroxy groupincludes inorganic esters such as phosphate esters and[alpha]-acyloxyalkyl ethers and related compounds which as a result ofthe in vivo hydrolysis of the ester breakdown to give the parent hydroxygroup. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. The present invention covers allsuch esters.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorph, in anyratio.

In accordance with a first aspect, the present invention coverscompounds of general formula (Ia):

-   in which A, R¹, R² and R³ have the meanings as defined in formula    (I), preferably R³ represents C₁-C₄-alkyl, more preferably methyl;-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Also preferred are compounds of general formula (I), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl; and-   in which R¹, R² and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Also preferred are compounds of general formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl; and-   in which R¹, R² and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Additionally preferred are compounds of general formula (I), wherein

-   R¹ represents C₁-C₄-alkyl, preferably methyl or ethyl; and-   in which A, R² and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Additionally preferred are compounds of general formula (Ia), wherein

-   R¹ represents C₁-C₄-alkyl, preferably methyl or ethyl; and-   in which A, R² and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Additionally preferred are compounds of general formula (I), wherein

-   R¹ represents a halogen atom, preferably chloro; and-   in which A, R² and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Additionally preferred are compounds of general formula (Ia), wherein

-   R¹ represents a halogen atom, preferably chloro; and-   in which A, R² and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Also preferred are compounds of general formula (I), more preferablycompounds of general formula (Ia), wherein

-   R³ represents C₁-C₄-alkyl, preferably methyl; and-   in which R¹, R² and A have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   R² represents —C₂-C₄-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl; and    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or more substituents which are the same or        different, at any ring carbon atom; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c);-   q represents an integer of 0; and-   in which A, R^(c), R¹ and R³ have the same meaning as defined in    general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   R² represents —C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl; and    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or more substituents which are the same or        different, at any ring carbon atom; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c);-   q represents an integer of 0; and-   in which A, R^(c), R¹ and R³ have the same meaning as defined in    general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   R² represents —C₂-C₄-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl; and    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or more substituents which are the same or        different, at any ring carbon atom; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c);-   q represents an integer of 0; and-   in which A, R^(c), R¹ and R³ have the same meaning as defined in    general formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   R² represents —C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl; and    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or more substituents which are the same or        different, at any ring carbon atom; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c);-   q represents an integer of 0; and-   in which A, R^(c), R¹ and R³ have the same meaning as defined in    general formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof general formula (I), wherein

-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or more substituents which are the same or    different, at any ring carbon atom; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl; and-   q represents an integer of 1; and-   in which A, R^(c), R¹ and R³ have the same meaning as defined in    general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof general formula (I), wherein

-   R² represents-(CH₂)_(q)-morpholinyl, wherein the ring nitrogen atom    is substituted with R^(c); and-   R^(c) represents methyl;-   q represents an integer of 1; and-   in which A, R¹ and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof general formula (Ia), wherein

-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or more substituents which are the same or    different, at any ring carbon atom; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl; and-   q represents an integer of 1; and-   in which A, R^(c), R¹ and R³ have the same meaning as defined in    general formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof general formula (Ia), wherein

-   R² represents-(CH₂)_(q)-morpholinyl, wherein the ring nitrogen atom    is substituted with R^(c); and-   R^(c) represents methyl;-   q represents an integer of 1; and-   in which A, R¹ and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   -   R² represents —C₂-C₄-alkyl-OH; and

-   in which A, R¹ and R³ have the same meaning as defined in general    formula (I),

-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   -   R² represents —C₂-C₄-alkyl-OH; and

-   in which A, R¹ and R³ have the same meaning as defined in general    formula (Ia),

-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl; and-   R¹ represents C₁-C₄-alkyl, preferably methyl or ethyl; and-   in which R² and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl; and-   R¹ represents C₁-C₄-alkyl, preferably methyl or ethyl; and-   in which R² and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl; and-   R¹ represents a halogen atom, preferably chloro; and-   in which R² and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl; and-   R¹ represents a halogen atom, preferably chloro; and-   in which R² and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Also preferred are compounds of general formula (I), more preferablycompounds of general formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl; and-   R³ represents C₁-C₄-alkyl, preferably methyl; and-   in which R¹ and R² have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Additionally preferred are compounds of general formula (I), morepreferably compounds of general formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl;-   R¹ represents C₁-C₄-alkyl, preferably methyl or ethyl; and-   R³ represents C₁-C₄-alkyl, preferably methyl; and-   in which R² has the same meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Additionally preferred are compounds of general formula (I), morepreferably compounds of general formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl;-   R¹ represents a halogen atom, preferably chloro; and-   R³ represents C₁-C₄-alkyl, preferably methyl; and-   in which R² has the same meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

A preferred embodiment relates to compounds of general formula (I), morepreferably compounds of general formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl;-   R¹ represents C₁-C₄.alkyl, preferably methyl or ethyl;-   R² represents —C₂-C₄-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl; and    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or more substituents which are the same or        different, at any ring carbon atom; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c);-   R³ represents C₁-C₄-alkyl, preferably methyl; and-   q represents an integer of 0,-   wherein R^(c) is defined as in formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

A preferred embodiment relates to compounds of general formula (I), morepreferably compounds of general formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl;-   R¹ represents C₁-C₄.alkyl, preferably methyl or ethyl;-   R² represents —C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl; and    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or more substituents which are the same or        different, at any ring carbon atom; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and-   R³ represents C₁-C₄-alkyl, preferably methyl; and-   q represents an integer of 0,-   wherein R^(c) is defined as in formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

A preferred embodiment relates to compounds of general formula (I), morepreferably compounds of general formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl;-   R¹ represents C₁-C₄.alkyl, preferably methyl or ethyl;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or more substituents which are the same or    different, at any ring carbon atom; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); wherein —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   R³ represents C₁-C₄-alkyl, preferably methyl; and-   q represents an integer of 1;-   wherein R^(c) is defined as in formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

A preferred embodiment relates to compounds of general formula (I), morepreferably compounds of general formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl;-   R¹ represents C₁-C₄.alkyl, preferably methyl or ethyl;-   R² represents —(CH₂)_(q)-morpholinyl, wherein the ring nitrogen atom    is substituted with R^(c); and-   R^(c) represents methyl;-   R³ represents C₁-C₄-alkyl, preferably methyl; and-   q represents an integer of 1;-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

A preferred embodiment relates to compounds of general formula (I), morepreferably compounds of general formula (Ia), wherein

-   A represents an optionally substituted 5- or 6-membered heteroaryl,    preferably an optionally substituted 6-membered heteroaryl;-   R¹ represents a halogen atom, preferably chloro;-   R² represents —C₂-C₄-alkyl-OH, preferably 3-hydroxybutan-2-yl;-   R³ represents C₁-C₄-alkyl, preferably methyl;-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Another preferred embodiment relates to compounds of general formula(I), more preferably compounds of general formula (Ia), wherein

-   A represents 5- or 6-membered heteroaryl at least containing one or    two nitrogen atom(s), preferably a 6-membered heteroaryl with one or    two nitrogen atom(s),    -   wherein said 5- or 6-membered heteroaryl is optionally        substituted one or two times, identically or differently, with a        substituent selected from a fluorine or chlorine atom,        C₁-C₂-alkyl, optionally substituted with 1-5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1-5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —C₂-C₃-alkyl-OR⁴, unsubstituted    —CH₂—(C₃-C₄-cycloalkyl), unsubstituted C₃-C₄-cycloalkyl,    unsubstituted (CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl;-   R³ represents methyl; and-   q represents an integer of 0,-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Another preferred embodiment relates to compounds of general formula(I), more preferably compounds of general formula (Ia), wherein

-   A represents 5- or 6-membered heteroaryl at least containing one or    two nitrogen atom(s), preferably a 6-membered heteroaryl with one or    two nitrogen atom(s),    -   wherein said 5- or 6-membered heteroaryl is optionally        substituted one or two times, identically or differently, with a        substituent selected from a fluorine or chlorine atom,        C₁-C₂-alkyl, optionally substituted with 1-5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1-5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents optionally substituted (CH₂)_(q)-(4- to 6-membered    heterocycloalkyl), wherein —(CH₂)_(q)-(4- to 6-membered    heterocycloalkyl) is optionally substituted with one or more    substituents which are the same or different, at any ring carbon    atom; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); wherein —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   R³ represents methyl; and-   q represents an integer of 1,-   wherein R^(c) is defined as in formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Another preferred embodiment relates to compounds of general formula(I), more preferably compounds of general formula (Ia), wherein

-   A represents 5- or 6-membered heteroaryl at least containing one or    two nitrogen atom(s), preferably a 6-membered heteroaryl with one or    two nitrogen atom(s),    -   wherein said 5- or 6-membered heteroaryl is optionally        substituted one or two times, identically or differently, with a        substituent selected from a fluorine or chlorine atom,        C₁-C₂-alkyl, optionally substituted with 1-5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1-5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —(CH₂)_(q)-morpholinyl, wherein the ring nitrogen atom    is substituted with R^(c) as defined in formula (I), preferably    substituted with methyl;-   R³ represents methyl; and-   q represents an integer of 1,-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

Another preferred embodiment relates to compounds of general formula(I), more preferably compounds of general formula (Ia), wherein

-   A represents 5- or 6-membered heteroaryl at least containing one or    two nitrogen atom(s), preferably a 6-membered heteroaryl with one or    two nitrogen atom(s),    -   wherein said 5- or 6-membered heteroaryl is optionally        substituted one or two times, identically or differently, with a        substituent selected from a fluorine or chlorine atom,        C₁-C₂-alkyl, optionally substituted with 1-5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1-5 fluorine atoms;-   R¹ represents a chloro atom;-   R² represents —C₂-C₄-alkyl-OH, preferably 3-hydroxybutan-2-yl; and-   R³ represents methyl,-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents pyrimidinyl, pyridazinyl, pyridinyl, pyrazinyl,    thiazolyl or thiadiazolyl, preferably pyrimidinyl, pyridazinyl,    thiazolyl or thiadiazolyl, more preferably pyrimidinyl, pyridazinyl    or thiadiazolyl, wherein said pyrimidinyl, pyridazinyl, pyridinyl,    pyrazinyl, thiazolyl and thiadiazolyl are optionally substituted;    and-   in which R¹, R² and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents pyrimidinyl, pyridazinyl, pyridinyl, pyrazinyl,    thiazolyl or thiadiazolyl, preferably pyrimidinyl, pyridazinyl,    thiazolyl or thiadiazolyl, more preferably pyrimidinyl, pyridazinyl    or thiadiazolyl, wherein said pyrimidinyl, pyridazinyl, pyridinyl,    pyrazinyl, thiazolyl and thiadiazolyl are optionally substituted;    and-   in which R¹, R² and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents CF₃-pyrimidinyl, preferably 2-CF₃-pyrimidin-5-yl; and-   in which R¹, R² and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents CF₃-pyrimidinyl, preferably 2-CF₃-pyrimidin-5-yl; and-   in which R¹, R² and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents CF₃-pyridazinyl, preferably 6-CF₃-pyridazin-3-yl; and-   in which R¹, R² and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents CF₃-pyridazinyl, preferably 6-CF₃-pyridazin-3-yl; and-   in which R¹, R² and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   R² represents cyclopropylmethyl, tetrahydrofuran-3-yl,    tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl,    prop-2-yn-1-yl, but-2-yn-1-yl, oxetan-3-yl, tetrahydropyran-4-yl,    tetrahydro-2H-pyran-4-ylmethyl, pyridin-4-yl, pyridin-3-yl,    1,3,4-thiadiazol-2-yl, 1,3-thiazol-2-yl,    2,2-dimethyl-2-methoxyethyl, methoxyethyl, piperidin-4-yl,    pyrrolidin-3-yl or azetidin-3-yl which are optionally substituted,    preferably unsubstituted cyclopropylmethyl, unsubstituted    oxetan-3-yl, unsubstituted tetrahydrofuran-3-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   R² represents 3-hydroxybutan-2-yl, prop-2-yn-1-yl, but-2-yn-1-yl,    2,2-dimethyl-2-methoxyethyl, methoxyethyl; or    -   cyclopropylmethyl, tetrahydrofuran-3-yl,        tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl,        oxetan-3-yl, tetrahydropyran-4-yl,        tetrahydro-2H-pyran-4-ylmethyl, (4-methylmorpholin-2-yl)methyl,        pyridin-4-yl, pyridin-3-yl, 1,3,4-thiadiazol-2-yl,        1,3-thiazol-2-yl, piperidin-4-yl, pyrrolidin-3-yl or        azetidin-3-yl which are optionally substituted,    -   preferably unsubstituted cyclopropylmethyl, unsubstituted        oxetan-3-yl, unsubstituted (3R)-tetrahydrofuran-3-yl,        unsubstituted (3S)-tetrahydrofuran-3-yl,        [(2R)-4-methylmorpholin-2-yl]methyl,        [(2S)-4-methylmorpholin-2-yl]methyl,        (2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl,        (2S,3R)-3-hydroxybutan-2-yl or (2R,3S)-3-hydroxybutan-2-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   R² represents cyclopropylmethyl, tetrahydrofuran-3-yl,    tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl,    prop-2-yn-1-yl, but-2-yn-1-yl, oxetan-3-yl, tetrahydropyran-4-yl,    tetrahydro-2H-pyran-4-ylmethyl, pyridin-4-yl, pyridin-3-yl,    1,3,4-thiadiazol-2-yl, 1,3-thiazol-2-yl,    2,2-dimethyl-2-methoxyethyl, methoxyethyl, piperidin-4-yl,    pyrrolidin-3-yl or azetidin-3-yl which are optionally substituted,    preferably unsubstituted cyclopropylmethyl, unsubstituted    oxetan-3-yl, unsubstituted tetrahydrofuran-3-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   R² represents 3-hydroxybutan-2-yl, prop-2-yn-1-yl, but-2-yn-1-yl,    2,2-dimethyl-2-methoxyethyl, methoxyethyl; or    -   cyclopropylmethyl, tetrahydrofuran-3-yl,        tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl,        oxetan-3-yl, tetrahydropyran-4-yl,        tetrahydro-2H-pyran-4-ylmethyl, (4-methylmorpholin-2-yl)methyl,        pyridin-4-yl, pyridin-3-yl, 1,3,4-thiadiazol-2-yl,        1,3-thiazol-2-yl, piperidin-4-yl, pyrrolidin-3-yl or        azetidin-3-yl which are optionally substituted,    -   preferably unsubstituted cyclopropylmethyl, unsubstituted        oxetan-3-yl, unsubstituted (3R)-tetrahydrofuran-3-yl,        unsubstituted (3S)-tetrahydrofuran-3-yl,        [(2R)-4-methylmorpholin-2-yl]methyl,        [(2S)-4-methylmorpholin-2-yl]methyl,        (2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl,        (2S,3R)-3-hydroxybutan-2-yl or (2R,3S)-3-hydroxybutan-2-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (I), wherein

-   R² represents unsubstituted tetrahydrofuran-3-yl or unsubstituted    oxetan-3-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (I), wherein

-   R² represents unsubstituted (3R)-tetrahydrofuran-3-yl,    (3S)-tetrahydrofuran-3-yl or unsubstituted oxetan-3-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (I), wherein

-   R² represents unsubstituted (3R)-tetrahydrofuran-3-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (I), wherein

-   R² represents [(2R)-4-methylmorpholin-2-yl]methyl,    (2R,3R)-3-hydroxybutan-2-yl, or (2S,3S)-3-hydroxybutan-2-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (I), wherein

-   R² represents [(2R)-4-methylmorpholin-2-yl]methyl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (I), wherein

-   R² represents (2R,3R)-3-hydroxybutan-2-yl, or    (2S,3S)-3-hydroxybutan-2-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (Ia), wherein

-   R² represents unsubstituted tetrahydrofuran-3-yl or unsubstituted    oxetan-3-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (Ia), wherein

-   R² represents unsubstituted (3R)-tetrahydrofuran-3-yl,    (3S)-tetrahydrofuran-3-yl or unsubstituted oxetan-3-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (Ia), wherein

-   R² represents unsubstituted (3R)-tetrahydrofuran-3-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (Ia), wherein

-   R² represents [(2R)-4-methylmorpholin-2-yl]methyl,    (2R,3R)-3-hydroxybutan-2-yl or (2S,3S)-3-hydroxybutan-2-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (Ia), wherein

-   R² represents [(2R)-4-methylmorpholin-2-yl]methyl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In yet another preferred embodiment, the invention relates to compoundsof formula (Ia), wherein

-   R² represents (2R,3R)-3-hydroxybutan-2-yl, or    (2S,3S)-3-hydroxybutan-2-yl; and-   in which R¹, A and R³ have the same meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R¹ represents methyl or ethyl; and-   in which R² and R³ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R¹ represents methyl or ethyl; and-   in which R² and R³ have the meaning as defined in general formula    (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R³ represents a methyl group; and-   in which R¹ and R² have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R² represents —C₂-C₄-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl;    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   q represents an integer of 0; and-   in which R^(c), R¹ and R³ have the meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R² represents —C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl;    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   q represents an integer of 0; and-   in which R^(c), R¹ and R³ have the meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R² represents —C₂-C₄-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl;    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   q represents an integer of 0; and-   in which R^(c), R¹ and R³ have the meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R² represents —C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl;    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   q represents an integer of 0; and-   in which R^(c), R¹ and R³ have the meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein said —(CH₂)_(q)-(4 to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl; and-   q represents an integer of 1; and-   in which R^(c), R¹ and R³ have the meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R² represents —(CH₂)_(q)-morpholinyl, wherein the ring nitrogen atom    is substituted with R^(c); and-   R^(c) represents methyl; and-   q represents an integer of 1; and-   in which R¹ and R³ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein said —(CH₂)_(q)-(4 to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl; and-   q represents an integer of 1; and-   in which R^(c), R¹ and R³ have the meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R² represents —(CH₂)_(q)-morpholinyl, wherein the ring nitrogen atom    is substituted with R^(c); and-   R^(c) represents methyl; and-   q represents an integer of 1; and-   in which R¹ and R³ have the meaning as defined in general formula    (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R² represents —C₂-C₄-alkyl-OH; and-   in which R¹ and R³ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1-5 fluorine atoms, or C₁-C₂-alkoxy,        optionally substituted with 1-5 fluorine atoms;-   R² represents —C₂-C₄-alkyl-OH; and-   in which R¹ and R³ have the meaning as defined in general formula    (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl; and-   in which R² and R³ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl; and-   in which R² and R³ have the meaning as defined in general formula    (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R³ represents methyl; and-   in which R¹ and R² have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R² represents —C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)q-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl;    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   q represents an integer of 0; and-   in which R^(c), R¹ and R³ have the meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R² represents —C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, (CH₂)q-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl;    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   q represents an integer of 0; and-   in which R^(c), R¹ and R³ have the meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein said —(CH₂)_(q)-(4 to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   q represents an integer of 1; and-   in which R^(c), R¹ and R³ have the meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein said —(CH₂)_(q)-(4 to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   q represents an integer of 1; and-   in which R^(c), R¹ and R³ have the meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R² represents —C₂-C₄-alkyl-OH; and-   in which R¹ and R³ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R² represents —C₂-C₄-alkyl-OH; and-   in which R¹ and R³ have the meaning as defined in general formula    (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R³ represents methyl; and-   in which R² has the meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents chloro;-   R³ represents methyl; and-   in which R² has the meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R³ represents methyl;-   R² represents —C₂-C₄-alkyl-OR⁴, CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4 to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl,    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted one or two times, identically or differently, at any        ring carbon atom with a substituent selected from C₁-C₄-alkyl,        optionally substituted with 1-5 halogen atoms which are the same        or different, a halogen atom, —NR^(a)R^(b) or —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and-   q represents an integer of 0; and-   in which R^(c) and R¹ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R³ represents methyl;-   R² represents —C₂-C₃-alkyl-OR⁴, CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4 to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl,    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted one or two times, identically or differently, at any        ring carbon atom with a substituent selected from C₁-C₄-alkyl,        optionally substituted with 1-5 halogen atoms which are the same        or different, a halogen atom, —NR^(a)R^(b) or —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and-   q represents an integer of 0; and-   in which R^(c) and R¹ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R³ represents methyl;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH2)q-(4- to 6-membered heterocycloalkyl) is substituted with        Rc; and wherein said —(CH₂)_(q)-(4 to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   q represents an integer of 1; and-   in which R^(c) and R¹ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R³ represents methyl;-   R² represents —(CH₂)_(q)-morpholinyl, wherein the ring nitrogen atom    is substituted with R^(c); and-   R^(c) represents methyl;-   q represents an integer of 1; and-   in which R¹ has the meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R³ represents methyl;-   R² represents C₂-C₄-alkyl-OH, preferably 3-hydroxybutan-2-yl; and-   in which R¹ has the meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl,    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —C₂-C₄-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4 to 6-membered heterocycloalkyl) or    —C₂-C₄-alkynyl,    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   q represents an integer of 0; and-   in which R^(c) and R³ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl,    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —C₂-C₄-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4 to 6-membered heterocycloalkyl) or    —C₂-C₄-alkynyl,    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   q represents an integer of 0; and-   in which R^(c) and R³ have the meaning as defined in general formula    (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl,    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4 to 6-membered heterocycloalkyl) or    —C₂-C₄-alkynyl,    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   q represents an integer of 0; and-   in which R^(c) and R³ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl,    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4 to 6-membered heterocycloalkyl) or    —C₂-C₄-alkynyl,    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   q represents an integer of 0; and-   in which R^(c) and R³ have the meaning as defined in general formula    (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl,    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein said —(CH₂)_(q)-(4 to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   q represents an integer of 1; and-   in which R^(c) and R³ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl,    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —(CH₂)_(q)-morpholinyl, wherein the ring nitrogen atom    is substituted with R^(c); and-   R^(c) represents methyl;-   q represents an integer of 1; and-   in which R³ has the meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl,    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein said —(CH₂)_(q)-(4 to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   q represents an integer of 1; and-   in which R^(c) and R³ have the meaning as defined in general formula    (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl,    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —(CH₂)_(q)-morpholinyl, wherein the ring nitrogen atom    is substituted with R^(c); and-   R^(c) represents methyl;-   q represents an integer of 1; and-   in which R³ has the meaning as defined in general formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl,    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents chloro;-   R² represents C₂-C₄-alkyl-OH, preferably 3-hydroxybutan-2-yl; and-   in which R³ has the meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl,    -   wherein said 6-membered heteroaryl is optionally substituted one        or two times, identically or differently, with a substituent        selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents chloro;-   R² represents C₂-C₄-alkyl-OH, preferably 3-hydroxybutan-2-yl; and-   in which R³ has the meaning as defined in general formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl,    -   wherein said 5-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R³ represents methyl; and-   in which R² has the meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl,    -   wherein said 5-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents chloro;-   R³ represents methyl;-   in which R² has the meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl,    -   wherein said 5-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R² represents —C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl;    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c);-   R³ represents methyl;-   q represents an integer of 0; and-   in which R^(c) and R¹ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl,    -   wherein said 5-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); wherein said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   R³ represents methyl;-   q represents an integer of 1; and-   in which R^(c) and R¹ have the meaning as defined in general formula    (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl,    -   wherein said 5-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —C₂-C₃-alkyl-OR⁴, CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl,    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted one or two times, identically or differently, at any        ring carbon atom with a substituent selected from C₁-C₄-alkyl,        optionally substituted with 1-5 halogen atoms which are the same        or different, a halogen atom, —NR^(a)R^(b) or —COOR⁵; and    -   wherein independently any ring nitrogen atom of said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and-   q represents an integer of 0;-   in which R^(c) and R³ have the meaning as defined in general formula    (I), and-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl,    -   wherein said 5-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —C₂-C₃-alkyl-OR⁴, CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl,    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted one or two times, identically or differently, at any        ring carbon atom with a substituent selected from C₁-C₄-alkyl,        optionally substituted with 1-5 halogen atoms which are the same        or different, a halogen atom, —NR^(a)R^(b) or —COOR⁵; and    -   wherein independently any ring nitrogen atom of said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c);-   q represents an integer of 0; and-   in which R^(c) and R³ have the meaning as defined in general formula    (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl,    -   wherein said 5-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   q represents an integer of 1; and-   in which R^(c) and R³ have has the meaning as defined in general    formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (Ia), wherein

-   A represents a 5-membered heteroaryl, in particular thiazolyl or    thiadiazolyl,    -   wherein said 5-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   q represents an integer of 1; and-   in which R^(c) and R³ have has the meaning as defined in general    formula (Ia),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —C₂-C₃-alkyl-OR⁴, CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl,    -   wherein said —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionally        substituted with one or two substituents which are the same or        different, at any ring carbon atom and selected from the group        consisting of C₁-C₄-alkyl, optionally substituted with 1-5        halogen atoms which are the same or different, a halogen atom,        —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring        nitrogen atom, if present in said —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is substituted with R^(c); and-   R³ represents methyl; and-   q represents an integer of 0,-   in which R^(c) has the meaning as defined in general formula (I), or    an isomer, enantiomer, diastereomer, racemate, hydrate, solvate, or    a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl;-   R³ represents methyl; and-   q represents an integer of 1,-   in which R^(c) has the meaning as defined in general formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —(CH₂)_(q)-morpholinyl, wherein the ring nitrogen atom    is substituted with R^(c); and-   R^(c) represents methyl;-   R³ represents methyl; and-   q represents an integer of 1,-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 6-membered heteroaryl, in particular pyrimidinyl or    pyridazinyl;    -   wherein said 6-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents chloro;-   R² represents —C₂-C₄-alkyl-OH, preferably 3-hydroxybutan-2-yl; and-   R³ represents methyl,-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 5-membered heteroaryl, in particular a thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —C₂-C₃-alkyl-OR⁴, CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl, —(CH₂)_(q)-(4 to 6-membered heterocycloalkyl), or    —C₂-C₄-alkynyl wherein said —CH₂—(C₃-C₄-cycloalkyl),    C₃-C₄-cycloalkyl and —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl)    are optionally substituted with one or more substituents which are    the same or different, at any ring carbon atom and selected from the    group consisting of C₁-C₄-alkyl, optionally substituted with 1-5    halogen atoms which are the same or different, a halogen atom,    —NR^(a)R^(b) and —COOR⁵; and wherein independently any ring nitrogen    atom if present in said —(CH₂)_(q)-(4- to 6-membered    heterocycloalkyl) is substituted with R^(c); and-   R³ represents methyl; and-   q represents an integer of 0,-   in which R^(c) has the meaning as defined in formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds ofgeneral formula (I), more preferably to compounds of general formula(Ia), wherein

-   A represents a 5-membered heteroaryl, in particular a thiazolyl or    thiadiazolyl;    -   wherein said 5-membered heteroaryl is optionally substituted        with one or two substituents which are the same or different,        and selected from a fluorine or chlorine atom, C₁-C₂-alkyl,        optionally substituted with 1 to 5 fluorine atoms, or        C₁-C₂-alkoxy, optionally substituted with 1 to 5 fluorine atoms;-   R¹ represents methyl or ethyl;-   R² represents —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl); and    wherein (CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is optionally    substituted with one or two substituents which are the same or    different, at any ring carbon atom and selected from the group    consisting of C₁-C₄-alkyl, optionally substituted with 1-5 halogen    atoms which are the same or different, a halogen atom, —NR^(a)R^(b)    and —COOR⁵; and    -   wherein independently any ring nitrogen atom, if present in said        —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) is substituted        with R^(c); and wherein —(CH₂)_(q)-(4- to 6-membered        heterocycloalkyl) is preferably —(CH₂)_(q)-morpholinyl; and-   R³ represents methyl; and-   q represents an integer of 1,-   in which R^(c) has the meaning as defined in formula (I),-   or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate,    or a salt thereof, or a mixture of same.

The following compounds are disclosed, namely

-   1)    3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   2)    3-(cyclopropylmethoxy)-N-[(6-methylpyridazin-3-yl)methyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   3)    3-(cyclopropylmethoxy)-N-[(5-methylpyrazin-2-yl)methyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   4)    3-(cyclopropylmethoxy)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   5)    N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   6)    N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   7)    3-(cyclopropylmethoxy)-N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   8)    3-(cyclopropylmethoxy)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   9)    3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   10)    3-(cyclopropylmethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   11)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N—{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   12)    N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   13)    N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   14)    N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   15)    N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   16)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   17)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   18)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   19)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   20)    N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   21)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{[6-(trifluoromethyl)pyridazin-3-yl]methyl}benzamide-   22)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}benzamide-   23)    N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   24)    N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   25)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   26)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   27)    N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   28)    N-[(1R)-1-(5-methylpyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   29)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   30)    N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   31)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide-   32)    N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide-   33)    N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide-   34)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide-   35)    N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide-   36)    3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   37)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide-   38)    3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   39)    N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide-   40)    3-(but-2-yn-1-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   41)    3-(but-2-yn-1-yloxy)-N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   42)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   43)    N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   44)    N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   45)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   46)    N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   47)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   48)    3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   49)    N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   50)    N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   51)    N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   52)    3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{[6-(trifluoromethyl)pyridazin-3-yl]methyl}benzamide-   53)    3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}benzamide-   54)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   55)    N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   56)    N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   57)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   58)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   59)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   60)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   61)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide-   62)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide-   63)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   64)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide-   65)    N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   66)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   67)    N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   68)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   69)    N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   70)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   71)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   72)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   73)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   74)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   75)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   76)    N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   77)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   78)    N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   79)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   80)    N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   81)    N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   82)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   83)    N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   84)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   85)    3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   86)    N-[(1R)-1-(6-methoxypyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   87)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   88)    N-[(6-methoxypyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   89)    3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   90)    3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}benzamide-   91)    N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   92)    N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   93)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide-   94)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide-   95)    N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide-   96)    N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide-   97)    N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide-   98)    3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   99)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide-   100)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   101)    N-[(6-methylpyridazin-3-yl)methyl]-3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   102)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   103)    3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   104)    N-[(5-methylpyrazin-2-yl)methyl]-3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   105)    3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   106)    3-[(2-methylpyridin-4-yl)oxy]-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   107)    N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   108)    3-[(6-methylpyridin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   109)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   110)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   111)    3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   112)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(1,3-thiazol-2-yloxy)benzamide-   113)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(1,3-thiazol-2-yloxy)benzamide-   114)    N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(1,3-thiazol-2-yloxy)benzamide-   115)    N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)benzamide-   116)    3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   117)    3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]benzamide-   118)    N-[(6-methylpyridazin-3-yl)methyl]-3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-[5-(trifluoromethyl)-1,3-thiazol-2-yl]benzamide-   119)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide-   120)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   121)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   122)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   123)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   124)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide-   125)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide-   126)    N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide-   127)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   128)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   129)    3-(5-ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   130)    N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   131)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[(6-methylpyridin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   132)    N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   133)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   134)    N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   135)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   136)    3-(2-methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   137) tert-butyl    4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate-   138)    3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   139)    3-[(1-methylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   140)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   141)    3-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   142)    3-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   143)    3-[(1-methylazetidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   144)    3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   145)    3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   146) tert-butyl    6-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]-2-azaspiro[3.3]heptane-2-carboxylate-   147)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[5-(trifluoromethyl)pyrazin-2-yl]ethyl}benzamide-   148)    3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

Also disclosed are the following compounds, namely:

-   149)    3-(1-azabicyclo[2.2.2]oct-4-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   150)    3-[(1-acetylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   151)    N-{(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   152)    N-{(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   153)    N-{(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   154)    N-{(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   155)    3-{[(3S)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   156)    3-[(3-methyloxetan-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   157)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   158)    3-{[(3R)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   159)    3-(5-methyl-1,3-thiazol-2-yl)-5-[2-(1H-1,2,4-triazol-1-yl)ethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   160)    3-(5-methyl-1,3-thiazol-2-yl)-5-[2-(1H-1,2,4-triazol-1-yl)ethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   161)    3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   162) Trans Isomer 1;    3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   163) Trans Isomer 2;    3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   164)    N-{(1R)-1-[6-(difluoromethyl)pyridin-3-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide-   165)    3-{[trans-3-(dimethylamino)cyclobutyl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   166)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{[2-(trifluoromethyl)pyrimidin-5-yl]methyl}benzamide-   167)    3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{[2-(trifluoromethyl)pyrimidin-5-yl]methyl}benzamide-   168)    3-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   169)    3-(5-ethyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   170)    3-[(6-methylpyridazin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   171)    N-{(1R)-1-[6-(difluoromethyl)pyridin-3-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   172)    3-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   173)    3-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   174)    3-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   175)    3-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   176)    3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   177)    3-[(2R)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   178)    3-[(2R)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   179)    3-[(2R)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   180)    3-[(2S)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   181)    3-[(2S)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   182)    3-[(2S)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   183) Trans Isomer 1;    3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   184) Trans Isomer 1;    3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   185) Cis Isomer 1;    3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   186) Trans Isomer 1;    3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   187) Cis Isomer 2;    3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   188) Trans Isomer 2;    3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   189) Trans Isomer 2;    3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   190) tert-Butyl    (3R)-3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate,    as a mixture of diastereoisomers 191)    3-(but-2-yn-1-yloxy)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   192)    3-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   193) Enantiomer 1;    3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide-   194) Enantiomer 2;    3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide-   195) Enantiomer 1;    3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide-   196) Enantiomer 2;    3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide-   197) Diastereisomer 1;    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide-   198) Diastereisomer 1;    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide-   199) Diastereoisomer 2; 1;    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide-   200) Diastereoisomer 2;    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide-   201)    3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   202)    3-(2-azaspiro[3.3]hept-6-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   203)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-pyrrolidin-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   204)    3-{[3-fluoropiperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of cis isomers-   205) Diastereoisomer 1;    3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   206) Diastereoisomer 2;    3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   207) Cis Isomer 1;    3-(5-methyl-1,3-thiazol-2-yl)-5-{[2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   208) Cis Isomer 2;    3-(5-methyl-1,3-thiazol-2-yl)-5-{[2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   209)    3-{[2-methyl-2-azabicyclo[2.2.1]hept-5-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   210)    3-[(1-methylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   211)    3-[(1-methylazetidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   212)    3-[(3-fluoro-1-methylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a single unknown isomer-   213)    3-{[1-(dimethylamino)cyclopropyl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   214)    3-[(2-methyl-2-azaspiro[3.3]hept-6-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   215)    N-{(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl}-3-[(1-methylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   216)    3-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   217)    3-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   218)    3-{[(4aS,7R,7aR)-4-methyloctahydrocyclopenta[b][1,4]oxazin-7-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   219)    3-{[(4aS,7S,7aR)-4-methyloctahydrocyclopenta[b][1,4]oxazin-7-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   220) Diastereoisomer 1;    3-[(1-methylpiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   221) Diastereoisomer 2;    3-[(1-methylpiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   222) Cis Isomer 1;    3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-methyl-2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   223) Cis Isomer 2;    3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-methyl-2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   224)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)piperidin-4-yl]oxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   225)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   226) methyl    4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate-   227) ethyl    4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate-   228) ethyl    (3S)-3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]pyrrolidine-1-carboxylate-   229)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)azetidin-3-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   230) Cis Isomer 1;    3-[(−3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   231) Cis Isomer 2;    3-[(−3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   232)    3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   233)    3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   234)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   235)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   236)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   237)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   238)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   239)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   240)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   241)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   242)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   243)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   244)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   245)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   246)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   247)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   248)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   249)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   250)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   251)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   252)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   253)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   254)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   255)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   256)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   257)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   258)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   259)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   260)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   261)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   262)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   263)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   264)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   265)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide-   266)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   267)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide-   268)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide-   269)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   270)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide-   271)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide-   272)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   273)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide-   274)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide-   275)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   276)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   277)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   278)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   279)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   280)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   281)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   282)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   283)    3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   284)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   285)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   286)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   287)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   288)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   289)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide-   290)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   291)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   292)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   293)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   294)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   295)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   296)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   297)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   298)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   299)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   300)    3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   301)    3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   302)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   303)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   304)    3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   305)    3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   306)    3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   307)    3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-N-[(6-methylpyridazin-3-yl)methyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   308)    3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   309)    3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   310)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   311)    N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzamide-   312)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   313)    N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzamide-   314)    N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzamide-   315)    N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzamide-   316)    3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide-   317)    3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   318)    3-(5-chloro-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   319)    3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide-   320)    3-(5-chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   321)    3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   322)    3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide-   323)    3-(5-chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   324)    3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   325)    3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide-   326)    3-(5-chloro-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   327)    3-[(3-methyloxetan-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   328)    3-(2-hydroxy-2-methylpropoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   329)    3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of two diastereoisomers-   330) Diastereoisomer 1;    3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   331) Diastereoisomer 2;    3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   332)    3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of two diastereoisomers-   333) Diastereoisomer 1;    3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   334) Diastereoisomer 2;    3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   335)    3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of two diastereoisomers-   336) Diastereoisomer 1;    3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   337) Diastereoisomer 2;    3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   338)    3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of cis isomers-   339) Cis Isomer 1;    3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   340) Cis Isomer 2;    3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   341)    3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of two stereoisomers-   342) Stereoisomer 1;    3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   343) Stereoisomer 2;    3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   344)    3-[(7-isopropyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of two stereoisomers-   345) methyl    9-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate,    as a mixture of two stereoisomers-   346) tert-butyl    (2R)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate-   347)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   348)    3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   349) tert-butyl    (2S)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate-   350)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   351)    3-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   352)    3-(5-methyl-1,3-thiazol-2-yl)-5-[morpholin-2-ylethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of diastereoisomers-   353)    3-{[4-methylmorpholin-2-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of diastereoisomers-   354) Diastereoisomer 1;    3-(fluoropiperidin-3-yl)methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   355) Diastereoisomer 2;    3-(fluoropiperidin-3-yl)methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   356) Diastereoisomer 1;    3-{[3-fluoro-1-methylpiperidin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   357) Diastereoisomer 2;    3-{[3-fluoro-1-methylpiperidin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   358)    3-[(3-fluoroazetidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   359)    3-{[4,4-difluoropiperidin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of 2 diastereoisomers-   360)    3-{[(3R)-4-methylmorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   361)    3-{[(3S)-4-methylmorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   362)    3-{[(3S)-4-methylmorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   363)    3-{[(3R)-4-methylmorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   364)    3-{[4-fluoro-1-methylpyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of stereoisomers-   365)    3-{[4-fluoro-1-methylpyrrolidin-2-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide,    as a mixture of stereoisomers-   366)    3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   367)    3-(5-chloro-1,3-thiazol-2-yl)-5-{[(2R)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   368)    3-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{[2-(trifluoromethyl)pyrimidin-5-yl]methyl}benzamide-   369)    N-{(1R)-1-[6-(difluoromethyl)pyridin-3-yl]ethyl}-3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzamide-   370)    3-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   371)    3-[(3-fluoro-1-methylazetidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   372)    3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{[2-(trifluoromethyl)pyrimidin-5-yl]methyl}benzamide-   373)    3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   374)    3-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   375)    3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2S)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   376)    3-(5-chloro-1,3-thiazol-2-yl)-5-{[(2S)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   377)    3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2R)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   378)    3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   379)    3-{[(2R)-1-methylpyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   380)    3-[(1-methylpiperidin-4-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   381)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[(2R)-4-(propan-2-yl)morpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   382)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[(2S)-4-(propan-2-yl)morpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   383)    3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N—{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of 2 diastereoisomers-   384) Diastereoisomer 1;    3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   385) Diastereoisomer 2;    3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   386)    3-[(3-fluoro-1-methylazetidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   387)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3-fluoro-1-methylazetidin-3-yl)methoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide-   388)    3-{[(3R)-4-methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   389)    3-{[(3S)-4-methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   390)    3-{[(2R)-4-ethylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   391)    3-{[(2R)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}-5-(5-methy-1,3-thiazol-2-yl)-N—{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   392) methyl    (2R)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate-   393) methyl    (2S)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate-   394)    3-(azetidin-3-ylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   395)    3-{[(3R)-4-methyl-5-oxomorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   396)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3R)-5-oxomorpholin-3-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   397)    3-{[(5S)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   398)    3-{[(5R)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   399)    3-{[(2R)-4-methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   400)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[(2S)-5-oxomorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   401)    3-{[(2S)-4-methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   402)    3-{[(3S)-4-methyl-5-oxomorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   403)    3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3S)-5-oxomorpholin-3-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   404) tert-butyl    1-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate,    as a mixture of 2 diastereoisomers-   405)    3-[(5-isopropyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of 2 diastereoisomers-   406)    3-[(5-methyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of 2 diastereoisomers-   407)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-1-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of 2 diastereoisomers-   408)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(5-propyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,    as a mixture of 2 diastereoisomers-   409) methyl    1-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate,    as a mixture of 2 diastereoisomers-   410) ethyl    1-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate,    as a mixture of 2 diastereoisomers-   411)    3-{[(2S)-4-ethylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   412) tert-butyl    (2R)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate-   413)    3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   414)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2S)-morpholin-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   415)    3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   416)    3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   417)    3-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide-   418)    3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2S)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide-   419)    3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2R)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

Also disclosed are compounds, namely

-   3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N—{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N—{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   3-(5-Methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   3-(5-Ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N—{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   3-(5-Ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N—{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   3-(5-Ethyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N—{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide;-   3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N—{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide.

Preferred compounds are, namely

-   3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide.

An even more preferred compound is3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide.

Also preferred compounds are, namely

-   3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2R)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2R)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide.

An even more preferred compound is3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}-benzamide.

Also preferred compounds are, namely

-   Trans Isomer 2;    3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   Trans Isomer 1;    3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide;-   Trans Isomer 1;    3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   Cis Isomer 1;    3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   Cis Isomer 2;    3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   Trans Isomer 2;    3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   Cis Isomer 1;    3-[(−3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide;-   Cis Isomer 2;    3-[(−3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide;-   Cis Isomer 1; 3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-,    3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;-   Cis Isomer 2;    3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide.

An even more preferred compound is Cis Isomer 1;3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}-benzamide.

It is to be understood that the present invention relates also to anycombination of the preferred embodiments described above.

Synthesis of Compounds of General Formula (I)/(Ia) of the PresentInvention

Compounds of general formula (I) with the meaning of R¹-R³ and A asdefined in general formula (I), can be synthesized according to ageneral procedure depicted in Scheme 1 starting from synthons of theformula (II) or (IV) respectively.

In analogy, compounds of general formula (Ia) with the meaning of R¹-R³and A as defined in general formula (Ia), can be synthesized accordingto a general procedure depicted in Scheme 1 starting from synthons ofthe formula (II) or (IVa) respectively. Intermediates depicted inSchemes 2 and 3 having an ester moiety —C(O)OR′ are referred to asmethyl, ethyl or propyl ester, respectively (R′: methyl, ethyl, propyl).

A carboxylic acid of formula (II) may react with an amine of formula(III) by methods known to those skilled in the art to give the compoundsof the general formula (I).

The reaction takes place in that for example, a carboxylic acid offormula (II) is activated with reagents such as dicyclohexylcarbodiimide(DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI),N-hydroxybenzotriazole (HOBT),N-[(dimethylamino)-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methyliden]-N-methylmethanaminiumhexafluorophosphate (HATU) or propylphosphonic anhydride (T3P). Forexample, the reaction with HATU takes place in an inert solvent, such asN,N-dimethylformamide, dichloromethane or dimethyl sulfoxide in thepresence of the appropriate amine formula (III) and a tertiary amine(such as triethylamine or diisopropylethylamine) at temperatures between−30° C. and +60° C.

It is also possible to convert a carboxylic acid of the formula (II)into the corresponding carboxylic acid chloride with an inorganic acidchloride (such as phosphorus pentachloride, phosphorus trichloride orthionyl chloride) and then into the target compounds of the generalformula (I), in pyridine or an inert solvent (such asN,N-dimethylformamide), in the presence of the appropriate amine formula(III) and a tertiary amine (for example triethylamine) at temperaturesbetween −30° C. and +60° C.

In full analogy, a carboxylic acid of formula (II) may react with anamine of formula (IIIa) by methods known to those skilled in the art togive the compounds of the general formula (Ia).

In the same manner, the compounds of the general formula (I) can beobtained from boronic acid pinacol esters of the general formula (IV) byreaction with bromo-thiazoles of the formula (V) by methods known tothose skilled in the art in a suitable solvent (for exampleN,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethoxyethane andoptionally water) and addition of a base (such as triethylamine,potassium carbonate, caesium carbonate) and a catalyst-ligand mixture,for example of palladium(II) acetate/triphenylphosphine,tetrakis-(triphenylphosphine)palladium(0),bis(diphenylphosphino)ferrocenedichloro-palladium (II), at temperaturesbetween 10° C. and 120° C.

In analogy, the compounds of the general formula (Ia) can be obtainedfrom boronic acid pinacol esters of the general formula (IVa) byreaction with bromo-thiazoles of the formula (V).

The carboxylic acids of the general formula (II) can for example beobtained from esters of the formula (VI) by ester saponification in asuitable solvent or solvent mixture (for example methanol, ethanol ortetrahydrofuran) with addition of an aqueous solution of an alkali metalhydroxide, for example sodium hydroxide or lithium hydroxide, attemperatures between 10° C. and 60° C. (Scheme 2).

In the same manner, carboxylic acids formula (XII) can be obtained fromesters formula (X) (Scheme 3), and carboxylic acids formula (XX) fromesters formula (XXI) (Scheme 4).

Alternatively, carboxylic acids of the formula (II) can be obtained fromnitriles of the formula (XXXIV) by nitrile hydrolysis in a suitablesolvent or solvent mixture (for example dimethyl sulfoxide or ethanol)with addition of an aqueous solution of an alkali metal hydroxide, forexample sodium hydroxide, at temperatures between 80° C. and 130° C.(Scheme 5).

The compounds of the general formula (VI) can be obtained from boronicacid pinacol esters of the general formula (IX) by reaction withbromo-thiazoles of the general formula (V) (Scheme 2), analogously tothe synthesis of the compounds of formula (I) from the compounds formula(IV).

In the same manner, compounds of the formula (VII) can be obtained fromboronic pinacol esters formula (VIII) and bromo-thiazoles formula (V)(Scheme 2).

Alternatively, compounds of the general formula (VI) can be obtainedfrom phenols of the general formula (VII) by reaction with electrophilesR²-LG (LG: leaving group) of the general formula (XXIV) (Scheme 2), bymethods known to those skilled in the art in a suitable solvent (forexample N,N-dimethylformamide, acetonitrile, acetone, dimethylsulfoxide) in the presence of a base (for example potassium carbonateand caesium carbonate) at temperatures between 10° C. and 120° C.

A suitable leaving group may include, for example chloro, bromo, iodo,methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy ornonafluorobutanesulfonyloxy.

Additionally, phenols of the general formula (VII) may react withalcohols R²-LG (LG:OH) to give compounds of the general formula (VI)(Scheme 2), by methods known to those skilled in the art in a suitablesolvent (for example dichloromethane or tetrahydrofuran) in the presenceof triphenylphosphine and diisopropyl azodicarboxylate, at temperaturesbetween −20° C. and 40° C.

Alternatively, compounds of the general formula (VI) can be obtainedfrom phenols of the general formula (VII) by reaction with oxiranes ofthe general formula (XXV) (Scheme 2) as electrophiles (wherein R″, R′″can independently be H or C₁-C₄-alkyl), by methods known to thoseskilled in the art in a suitable solvent (for exampleN,N-dimethylformamide, acetonitrile or dimethyl sulfoxide) in thepresence of a base (for example potassium carbonate or caesiumcarbonate) at temperatures between 10° C. and 120° C.

In the same manner as described above, compounds of the formula (X) canbe obtained from 3-bromo-5-hydroxybenzoic acid ester of the formula(XXVI) and compounds of the formula (XXIV) or formula (XXV),respectively (Scheme 2).

In addition, compounds of the formula (VI) can also be obtained fromaryl bromides of the general formula (XXVIII) by reaction with aheteroaromatic alcohol of the formula (XXIV) (LG:OH, R²: 5-10-memberedheteroaromatic system), by methods known to those skilled in the art ina suitable solvent (for example N-methyl-2-pyrrolidinone) in thepresence of a base (for example potassium carbonate or caesiumcarbonate) and copper(I) chloride, by heating the reaction mixture in amicrowave, at temperatures between 100° C. and 220° C. (Scheme 2).

After workup and purification it may occur that by following thedescribed procedure a carboxylic acid of the general formula (II)instead of the before mentioned ester of formula (VI) is obtained.

The compounds of the general formula (XXXIV) can be obtained from arylfluorides of the formula (XXXII) by reaction with alcohols R₂—OH of thegeneral formula (XXXIII) (Scheme 5), by methods known to those skilledin the art in a suitable solvent (for example N,N-dimethylformamide) inthe presence of a base (for example sodium hydride) at temperaturesbetween 10° C. and 80° C.

Compounds of the general formula (XXXII) can be obtained from boronicacid pinacol esters of the general formula (XXXI) by reaction withbromo-thiazoles of the formula (V) (Scheme 5), analogously to thesynthesis of the compounds of formula (I) from the compounds formula(IV).

The compounds of the general formula (IV) can be obtained from arylbromides of the general formula (XI) by reaction withbis(pinacolato)diborane (Scheme 3) in a suitable solvent (for example1,4-dioxane) in the presence of potassium acetate and a catalyst (forexample 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)-dichloridedichloromethane complex or[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) attemperatures between 60° C. and 100° C.

In analogy, the compounds of the general formula (IVa) can be obtainedfrom aryl bromides of the general formula (XIa).

In the same manner, compounds of the formula (IX) can be obtained fromaryl bromides of general formula (X) and likewise compounds of thegeneral formula (VIII) can be obtained from 3-bromo-5-hydroxybenzoicacid esters of formula (XXVI) (Scheme 2).

Similarly, compounds of the general formula (XXXI) can be obtained fromaryl bromides of the general formula (XXX) (Scheme 5).

The compounds of the general formula (XI) can be obtained fromcarboxylic acids of the general formula (XII) by reaction with amines ofthe general formula (III) (Scheme 3), analogously to the synthesis ofthe compounds of formula (I) from carboxylic acids formula (II) andamines formula (III).

In analogy, the compounds of the general formula (XIa) can be obtainedfrom carboxylic acids of the general formula (XII) by reaction withamines of the general formula (IIIa).

Compounds of the general formula (XXVIII) can be obtained from arylbromides of the general formula (XXVII) by reaction with thiazoles ofthe formula (XXIX) (Met: e.g. tributylstannanyl) by methods known tothose skilled in the art in a suitable solvent (for exampleN,N-dimethylformamide) and addition of a base (for example potassiumcarbonate or caesium carbonate) and a catalyst-ligand mixture (forexample of palladium(II) acetate/triphenylphosphine,tetrakis(triphenyl-phosphine)palladium(0)) at temperatures between 40°C. and 120° C. (Scheme 2).

Amines of the general formula (IIIa) can be obtained from sulfinamidesof the general formula (XIII) or (XIV) by methods known to those skilledin the art in a suitable solvent (for example methanol, 2-propanol,diethyl ether) and addition of an acid (for example hydrochloric acid)at appropriate concentrations (e.g. 4M in dioxane, 3M in 2-propanol, 2Min diethyl ether, 12M in water) at temperatures between 0° C. and 40° C.(Scheme 4). The amines of the general formula (IIIa) may be obtained asthe mono, bis or tris salt (for example the hydrochloric/dihydrochloricsalts). Alternatively, the amine salt can be converted into the freebase by methods known to those skilled in the art.

Amines of the general formula (III) and (IIIa) can be used as the freebase or salt of undefined stoichiometry according to, but not limitedto, the synthetic disclosure herein to obtain compounds of the generalformula (I)/(Ia) and general formula (XI)/(XIa).

Sulfinamides of the general formula (XIII) can be obtained from ketonesof the general formula (XVII) which are converted in situ tosulfinimides of the general formula (XV) by methods known to thoseskilled in the art in a suitable solvent (for example diethyl ether,tetrahydrofuran) and addition of titanium(IV) ethoxide and(S)-2-tert-butylsulfinamide, at temperatures between 10° C. and 80° C.The sulfinimides (XV) can be directly converted to sulfinamides of theformula (XIII) by methods known to those skilled in the art in asuitable solvent (for example tetrahydrofuran) and the addition ofL-selectride, at temperatures between −80° C. and −70° C. (Scheme 4).

Sulfinamides of the general formula (XIV) can be obtained from aldehydesof the general formula (XVIII) which are converted to sulfinimides ofthe general formula (XVI) by methods known to those skilled in the artin a suitable solvent (for example dichloroethane) and addition ofCopper(II) sulfate and (R)-2-tert-butylsulfinamide, at temperaturesbetween 10° C. and 80° C. The sulfinimides (XVI) can be converted tosulfinamides of the formula (XIV) by methods known to those skilled inthe art in a suitable solvent (for example tetrahydrofuran, diethylether) and the addition of a Grignard reagent R³MgX (X: Cl, Br), attemperatures between −70° C. and −20° C. (Scheme 4).

Amines having the opposite stereochemistry to the stereochemistrydescribed for amines of the general formula (IIIa) can be synthesized inanalogous fashion as described for amines (IIIa) starting from ketone(XVII) and using (R)-2-tert-butylsulfinamide instead of(S)-2-tert-butylsulfinamide. In a similar fashion, starting fromaldehyde (XVIII) and using (S)-2-tert-butylsulfinamide instead of(R)-2-tert-butylsulfinamide.

Ketones of the general formula (XVII) can be obtained from Weinrebamides of the general formula (XIX) by methods known to those skilled inthe art in a suitable solvent (for example tetrahydrofuran, diethylether, tert-butyl methyl ether or toluene) and the addition of aGrignard reagent R³MgX (X: Cl, Br, I), at temperatures between −20° C.and 0° C. (Scheme 4).

Likewise, ketones of the general formula (XVII) can be obtained fromnitriles of the general formula (XXII) and a Grignard reagent R³MgX (X:Cl, Br, I).

In addition, ketones of the general formula (XVII) can be obtained fromhalides of the general formula (XXIII) (Hal: Cl, Br) by methods known tothose skilled in the art in a suitable solvent (for exampleN,N-dimethylformamide), tributyl(1-ethoxy-vinyl)stannane and a catalyst(for example dichlorobis(triphenylphosphine)-palladium(II)), attemperatures between 40° C. and 100° C. and subsequent cleavage of theenol ether intermediate under acidic conditions (for example aqueoushydrochloric acid), in a suitable solvent (for example tetrahydrofuran)at temperatures between 10° C. and 40° C. (Scheme 4).

Weinreb amides of the general formula (XIX) can be obtained fromcarboxylic acids of the general formula (XX) and N-methoxymethaneaminein analogous fashion as described for amides of formula (I) fromcarboxylic acids of formula (II).

Aldehydes of the general formula (XVIII) can be obtained from amides ofthe formula (XIX) by reduction methods known to those skilled in the artin a suitable solvent (for example tetrahydrofuran) and a reducing agent(for example lithium aluminium hydride) at temperatures between −80° C.and −70° C. (Scheme 4).

Bromo-thiazoles of the general formula (V) can be generated fromamino-thiazoles of the formula (XXXV) by methods known to those skilledin the art in a suitable reaction medium (for example aqueoushydrobromic acid/sodium nitirite, copper(II) bromide/tert-butyl nitrite)in acetonitrile or N,N-dimethylformamide at temperatures between 0° C.and 40° C. (Scheme 4).

Additionally, compounds of the general formula Ia, IIIa, IVa and XIa canbe obtained directly from their racemic respectively diastereoisomericmixtures of the general formula I, III, IV and XI through separation ofsaid mixtures using methods known to someone skilled in the art (e.g.preparative chiral HPLC).

EXPERIMENTAL SECTION

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

The following table lists the abbreviations used in this paragraph, andin the examples section.

Abbreviation Meaning Cs₂CO₃ Cesium carbonate Cu(I)Cl Copper(I) chlorideca. circa DCE 1,2-Dichloroethane DCM Dichloromethane DIAD Diisiopropylazodicarboxylate DIPEA N-Ethyl-N-isopropylpropan-2-amine DIADDiisopropyl azodicarboxylate DMA Dimethylacetamide DMAPN,N-Dimethylpyridin-4-amine DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide DP Desired product EE Ethyl acetate EEDQN-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline EtOAc Ethyl acetate EtOHEthanol Et₂O Diethyl ether h Hour(s) HATUN-[(Dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N- methylmethanaminium hexafluorophosphateHBr Hydrogen bromide HCl Hydrochloric acid HPLC high performance liquidchromatography IPA 2-Propanol IPC In process check K₂CO₃ Potassiumcarbonate KOtBu Potassium 2-methylpropan-2-olate LC-MS liquidchromatography-mass spectrometry LCMS liquid chromatography-massspectrometry LiOH Lithium hydroxide M Molar μW Microwave MeCNAcetonitile MeOH Methanol MgSO₄ Magnesium sulfate min Minute(s) N NormalNaBH₄ Sodium tetrahydroborate Na₂CO₃ Sodium carbonate NaH Sodium hydrideNaHCO₃ Sodium bicarbonate NaI Sodium iodide NaOH Sodium hydroxide Na₂SO₄Sodium sulfate NH₄Cl Ammonium chloride NMP N-Methyl-2-pyrrolidinone NMRnuclear magnetic resonance spectroscopy PdCl₂(PPh₃)₂Bis(triphenylphosphine)palladium(II) dichloride Pd(dppf)Cl₂[1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II)Pd(dppf)Cl₂•CH₂Cl₂ 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex PPh₃ Triphenylphosphineppm parts per million RT Room temperature rt Retention time Rt Retentiontime sat. Saturated SM Starting material STAB Sodiumtriacetoxyborohydride T3P Propylphosphonic anhydride TBAITetra-N-butylammonium iodide TBME tert-Butyl methyl ether TEATriethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TMS—BrTrimethylsilyl bromideAnalysis MethodsLC-MS, Method A: Routine High Throughput Analysis

Column Supelco Ascentis Express 2.1 × 30 mm, 2.7 μm Available on MS14,MS17, MS18 and MS19 Column 40° C. Temp Mobile Phase A, Water + 0.1%Formic acid B, Acetonitrile + 0.1% Formic acid Time (mins) % organicGradient 0 5 1.5 100 1.6 100 1.61 5 Flow rate 1 ml/min Injection Vol 3μl Detection Signal UV 215 PDA Range: 210-420 nm step: 1 nm Spectrum(Not MS14 this has single wavelength detector) MSD Signal Scan Pos(Shimadzu): 100-1000 settings Scan Pos (MS14): 130-850LC-MS, Method B: Routine High Throughput Analysis

Column Waters Atlantis dC18 2.1 × 50 mm, 3 μm Available on MS11, MS14,MS17, MS18 and MS19 Column 40° C. Temp Mobile Phase A, Water + 0.1%Formic acid B, Acetonitrile + 0.1% Formic acid Time (mins) % organicGradient 0.00 5 2.50 100 2.70 100 2.71 5 3.50 5 Flow rate 1 ml/minInjection Vol 3 μl Detection Signal UV 215 PDA Range: 210-420 nm step: 1nm Spectrum (Not MS14 this has single wavelength detector) MSD SignalScan Pos (Shimadzu): 100-1000 settings Scan Pos (MS14): 130-850LC-MS, Method C: Routine High Throughput Analysis at High pH

Column Phenomenex Gemini-NX C18 2.0 × 50 mm, 3 um Available on MS10Column 40° C. Temp Mobile Phase A, 2 mM amm. bicarbonate, buffered to pH10 B, Acetonitrile Time (mins) % organic Gradient 0.00 1 1.80 100 2.10100 2.30 1 3.50 1 Flow rate 1 ml/min Injection Vol 3 μl Detection SignalUV 215 PDA Range: 210-420 nm step: 1 nm Spectrum MSD Signal Scan Pos:150-850 settingsLC-MS, Analytical Method D:

Column Waters Atlantis dC18 2.1 × 100 mm, 3 μm Available on MS11, MS17,MS18 and MS19 Column 40° C. Temp Mobile Phase A, Water + 0.1% Formicacid B, Acetonitrile + 0.1% Formic acid Time (mins) % organic Gradient0.00 5 5.00 100 5.40 100 5.42 5 7.00 5 Flow rate 0.6 ml/min InjectionVol 3 μl Detection Signal UV 215 PDA Range: 210-420 nm step: 1 nmSpectrum MSD Signal Scan Pos: 100-1000 settingsLC-MS, Analytical Method E: High pH

Column Phenomenex Gemini-NX C18 2.0 × 100 mm, 3 μm column Available onMS10 Column 40° C. Temp Mobile Phase A, 2 mM amm. bicarbonate, bufferedto pH 10 B, Acetonitrile Time (mins) % organic Gradient 0.00 5 5.50 1005.90 100 5.92 5 7.00 5 Flow rate 0.5 ml/min Injection Vol 3 μl DetectionSignal UV 215 PDA Range: 210-420 nm step: 1 nm Spectrum MSD Signal ScanPos: 100-1000 settingsLC-MS, Analytical Method F:

Column Phenomenex Kinetix-XB C18 2.1 × 100 mm, 1.7 μm Available on MSQ1Column 40° C. Temp Mobile Phase A, Water + 0.1% Formic acid B,Acetonitrile + 0.1% Formic acid Time (mins) % organic Gradient 0.00 55.30 100 5.80 100 5.82 5 7.00 5 Flow rate 0.6 ml/min Injection Vol 1 μlDetection Signal UV 215 PDA Range: 200-400 nm step: 1 nm Spectrum MSDSignal Scan Pos: 150-850 settingsAnalytical LCMS Method 1, Low pH:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEHC18 1.7 50×2.1 mm; eluent A: water+0.1 vol % formic acid (99%), eluentB: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Analytical LCMS Method 2, High pH:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEHC18 1.7 50×2.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%),eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B;flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Chiral Analysis Methods:

Detector Flow rate wavelength Method Column Type (ml/min) (nm) IsocraticConditions 1 Amy-C (4.6 mm × 4 210-400 20:80 MeOH/CO₂ 250 mm, 5 um) 2Lux C3 (4.6 mm × 4 210-400 2:8 MeOH/CO₂ (0.1% 250 mm, 5 um) v/v NH₃) 3Lux C4 (4.6 mm × 4 210-400 25:75 MeOH/CO₂ 250 mm, 5 um) 4 Lux C4 (4.6 mm× 1 210-400 50:50 Heptane/IPA 250 mm, 5 um) (DEA added as a modifier) 5Amy-C (4.6 mm × 4 210-400 25:75 EtOH/CO₂ 250 mm, 5 um) (0.1% v/v NH₃) 6Lux C1 (4.6 mm × 4 210-280 3:7 MeOH/CO₂ (0.1% 250 mm, 5 um) v/v DEA) 7Amy-C (4.6 mm × 21 210-400 25:75 MeOH/CO₂ 250 mm, 5 um) (0.1% v/v NH₃) 8Amy-C (4.6 mm × 4 210-400 40:60 EtOH/CO₂ 250 mm, 5 um) (0.1% v/v NH₃) 9Amy-C (4.6 mm × 1 254 60:40 Heptane/IPA 250 mm, 5 um) (0.1% v/v NH₃) 10Amy-C (4.6 mm × 4 210-400 35:65 MeOH/CO₂ 250 mm, 5 um) (0.1% v/v NH₃) 11Lux C1 (4.6 mm × 1 220 70:30 Heptane/EtOH 250 mm, 5 um) (0.1% v/v DEA)12 Lux C1 (4.6 mm × 1 220 40:60 Heptane/EtOH 250 mm, 5 um) (0.1% v/vDEA) 13 Amy-C (4.6 mm × 4 210-400 30:70 MeOH/CO2 250 mm, 5 um) (0.1% v/vNH₃) 14 Amy-C (4.6 mm × 4 210-400 20:80 MeOH/CO2 250 mm, 5 um) (0.1% v/vNH₃) 15 Amy-C (4.6 mm × 4 210-400 25:75 MeOH/CO2 250 mm, 5 um) (0.1% v/vNH₃) 16 Amy-C (4.6 mm × 4 210-400 10:90 to 50:50 250 mm, 5 um) MeOH/CO2(0.1% v/v NH₃)Analytical chiral HPLC MethodsMethod A:

Instrument: Agilent HPLC 1260; Column: Chiralpak IE 3μ 100×4.6 mm;Eluent A: tert-butyl methyl ether+0.1 Vol-% diethylamine (99%); EluentB: ethanol; isokratic: 95% A+5% D; flow 1.4 ml/min; temperature: 25° C.;DAD 325 nm

Method B:

Instrument: Agilent: 1260, Aurora SFC-Module; column: Chiralpak IF 5 μm100×4.6 mm; eluent A: CO₂, eluent B: ethanol; isokratic: 16% B; flow 4.0ml/min; temperature: 37.5° C.; BPR: 100 bar; MWD @ 254 nm

Method C:

Instrument: Agilent HPLC 1260; column: Chiralpak IC 3μ 100×4.6 mm;eluent A: hexane; eluent B: 2-propanol; isokratic: 70% A+30% B; flow 1.0ml/min; temperature: 25° C.; DAD@ 254 nm

Method D:

Instrument: Agilent HPLC 1260; column: Chiralpak IC 3μ 100×4.6 mm;eluent A: hexane+0.1 Vol-% diethylamine (99%); eluent B: ethanol;isokratic: 80% A+20% B; flow 1.0 ml/min; temperature: 25° C.; DAD 254 nm

Method E:

Instrument: Agilent HPLC 1260; column: Chiralpak IC 3μ 100×4.6 mm;eluent A: hexane+0.1 Vol-% diethylamine (99%); eluent B: ethanol;isokratic: 50% A+50% B; flow 1.4 ml/min; temperature: 25° C.; DAD 254 nm

Method F:

Instrument: Agilent: 1260, Aurora SFC-Module; column: LUNA HILIC 5 μm100×4.6 mm; eluent A: CO₂, eluent B: methanol+0.2 Vol-% diethylamine(99%); isokratic: 20% B; flow 4.0 ml/min; temperature: 37.5° C.; BPR:100 bar; MWD @ 254 nm

Method G:

Instrument: Agilent HPLC 1260; column: Chiralpak IF 3μ 100×4.6 mm;Eluent A: water, Eluent B: acetonitrile; isocratic: 70% A+30% B; flow1.4 ml/min; temperature: 25° C.; MWD @ 220 nm

Purification Methods:

Biotage Isolera™ chromatography system using pre-packed silica andpre-packed modified silica cartridges.

Preparative HPLC, Method A: High pH

Column Waters Xbridge C18 30 × 100 mm, 10 um Available on Gilson 3 andGilson5 Column Room temperature Temp Mobile Phase A, Water + 0.2%Ammonium hydroxide B, Acetonitrile + 0.2% Ammonium hydroxide Time (mins)% organic Gradient 0 5 2.5 5 16.05 95 18.2 95 19.1 5 20 5 Flow rate 40ml/min Injection Vol 1500 μl Detection Signal UV 215Preparative HPLC, Method B: Low pH

Column Waters Sunfire C18 30 × 100 mm, 10 um Available on Waters02Column Room temperature Temp Mobile Phase A, Water + 0.1% Formic acid B,Acetonitrile + 0.1% Formic acid Time (mins) % organic Gradient 0 5 2 52.5 10 14.5 100 15.5 100 16 5 17 5 Flow rate 40 ml/min Injection Vol1500 μl Detection Signal UV 215Preparative HPLC MethodsPreparative HPLC, Method 1:

System: Waters autopurification system: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5 μm 100×30 mm;Solvent: A=H2O+0.1% Vol. formic acid (99%), B=acetonitrile; Gradient:0-8 min 10-100% B, 8-10 min 100% B; Flow: 50 mL/min; temperature: roomtemp.; Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF; Injection: 1×2.5mL; Detection: DAD scan range 210-400 nm; MS ESI+, ESI−, scan range160-1000 m/z.

Preparative HPLC, Method 2:

System: Waters autopurification system: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5 μm 100×30 mm;Solvent: A=H2O+0.1% Vol. ammonia (99%), B=acetonitrile; Gradient: 0-8min 10-100% B, 8-10 min 100% B; Flow: 50 mL/min; temperature: roomtemp.; Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF; Injection: 1×2.5mL; Detection: DAD scan range 210-400 nm; MS ESI+, ESI−, scan range160-1000 m/z.

Chiral Purification Methods:

Detector Flow wave- rate length Isocratic Method Column Type (ml/min)(nm) Conditions 1 Amy-C (20 mm × 50 210 20:80 MeOH/CO₂ 250 mm, 5 um) 2Lux C3 (21.2 mm × 50 210 20:80 MeOH/CO₂ 250 mm, 5 um) (0.1% v/v NH₃) 3Lux C4 (20 mm × 50 210 25:75 MeOH/CO₂ 250 mm, 5 um) 4 Lux C4 (20 mm × 21212 50:50 Heptane/IPA 250 mm, 5 um) (DEA added as a modifier) 5 Amy-C(20 mm × 50 210 25:75 EtOH/CO₂ 250 mm, 5 um) 6 Lux C1 (20 mm × 50 21525:75 MeOH/CO₂ 250 mm, 5 um) (0.1% v/v DEA) 7 Amy-C (20 mm × 50 21025:75 MeOH/CO₂ 250 mm, 5 um) (0.1% v/v NH₃) 8 Amy-C (20 mm × 50 21040:60 EtOH/CO₂ 250 mm, 5 um) (0.1% v/v NH₃) 9 Amy-C (20 mm × 42 21070:30 Heptane/IPA 250 mm, 5 um) (0.1% v/v NH₃) 10 Amy-C (20 mm × 50 22035:65 MeOH/CO₂ 250 mm, 5 um) (0.1% v/v NH₃) 11 Lux C1 (20 mm × 21 22070:30 Heptane/ 250 mm, 5 um) EtOH (0.1% v/v DEA) 12 Lux C1 (20 mm × 21220 50:50 Heptane/ 250 mm, 5 um) EtOH (0.1% v/v DEA) 13 Amy-C (20 mm ×50 210 25:75 MeOH/CO2 250 mm, 5 um) (0.1% v/v NH₃) 14 Amy-C (20 mm × 50210 15:85 MeOH/CO2 250 mm, 5 um) (0.1% v/v NH₃) 15 Amy-C (20 mm × 50 21525:75 MeOH/CO2 250 mm, 5 um) (0.1% v/v NH₃)Preparative Chiral HPLC MethodsMethod A:

Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario4000; column: Chiralpak IE 5μ 250×30 mm; eluent A: ethanol+0.1 Vol-%diethylamine (99%); eluent B: tert.-butyl methyl ether; isokratic: 5%A+95% B; flow 50.0 ml/min; UV 325 nm

Method B:

Instrument: Sepiatec: Prep SFC100; column: Chiralpak IF 5 μm 250×30 mm;eluent A: CO₂, eluent B: ethanol; isokratic: 16% B; flow 100.0 ml/min;temperature: 40° C.; BPR: 150 bar; MWD @ 254 nm

Method C:

Instrument: Agilent PrepHPLC 1200, column: Chiralpak IC 5μ 250×20 mm;eluent A: hexane; eluent B: 2-propanol; isokratic: 70% A+30% B; flow15.0 ml/min; UV@ 254 nm

Method D:

Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario4000, column: Chiralpak IC 5μ 250×30 mm; eluent A: hexane+0.1 Vol-%diethylamine (99%); eluent B: ethanol; isokratic: 80% A+20% B; flow 50.0ml/min; UV 254 nm

Method E:

Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario4000, column: Chiralpak IC 5μ 250×30 mm; eluent A: hexane+0.1 Vol-%diethylamine (99%); eluent B: ethanol; isokratic: 70% A+30% B; flow 50.0ml/min; UV 254 nm

Method F:

Instrument: Sepiatec: Prep SFC100; column: LUNA HILIC 5 μm 250×30 mm;eluent A CO₂, eluent B: methanol+0.5 Vol-% ammonia (32%); isokratic: 20%B; flow 100.0 ml/min temperature: 40° C.; BPR: 90 bar; MWD @ 254 nm

EXAMPLES

Chemical naming of the Examples and Intermediates was performed usingACD software by ACD/LABS or Marvin software by ChemAxon.

Reaction times are either specified explicitly in the protocols of theexperimental section, or reactions were run until completion. Chemicalreactions were monitored and their completion was judged using methodswell known to the person skilled in the art, such as thin layerchromatography, e.g. on plates coated with silica gel, or by LCMSmethods.

Intermediate 1 Methyl 3-bromo-5-hydroxybenzoate

A solution of 3-bromo-5-hydroxybenzoic acid (47.7 g, 0.22 mol) andacetyl chloride (31.5 mL, 0.44 mol) in methanol (500 mL) was stirredunder reflux for 16 h. TLC analysis indicated complete conversion to asingle product. The solvent was removed under reduced pressure to give49.9 g (98% yield) of the title compound as an off-white powder, usedwithout further purification in the next step.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.74 (t, J=1.5 Hz, 1H), 7.46(dd, J=2.4, 1.3 Hz, 1H), 7.25-7.16 (m, 1H), 5.57 (s, 1H), 3.92 (s, 3H).

Intermediate 2 Methyl3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Methyl 3-bromo-5-hydroxybenzoate (26 g, 112.5 mmol),bis(pinacolato)diborane (31.4 g, 123.8 mmol) and potassium acetate (33.1g, 337.6 mmol) were dissolved in 1,4-dioxane (450 mL) and the solutiondegassed with a stream of nitrogen for 10 min. Pd(dppf)Cl₂.CH₂Cl₂ (4.6g, 5.62 mmol) was added and the resulting solution degassed with astream of nitrogen for a further 5 min before the reaction mixture wasstirred at 100° C. for 16 h. The reaction mixture was filtered throughCelite® and concentrated in vacuo to give a brown solid. The crudematerial was purified by dry flash silica chromatography (eluting with0-25% EtOAc in heptanes). Product containing fractions wereconcentrated, the material slurried in heptane and the solid collectedby filtration to give the title compound 30.1 g (96% yield) as a creampowder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.04 (s, 1H), 7.60 (dd, J=2.7,1.5 Hz, 1H), 7.47-7.41 (m, 1H), 4.95 (s, 1H), 3.90 (s, 3H), 1.35 (s,12H).

Intermediate 3 Methyl 3-hydroxy-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 2 (1.0 g, 3.60 mmol) and 2-bromo-5-methyl-1,3-thiazole(0.451 mL, 4.32 mmol) were dissolved in 1M K₂CO₃ aqueous solution (8.63mL) and THF (58.7 mL). The solution was degassed with a stream ofnitrogen for 10 minutes,[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (395.3mg, 0.539 mmol) was added and the reaction mixture heated at 90° C. for17 h until reaction completion (monitored by TLC). The reaction mixturewas diluted with water (100 mL) and extracted with EtOAc (3×100 mL). Thecombined organics were dried (over MgSO₄) and concentrated under reducedpressure. Crude material was purified by Biotage Isolera™ chromatography(eluting with 12-80% EtOAc in heptane on a 25 g pre-packed KP-SiO₂column) to give 359.7 mg (40% yield) of the title compound as anoff-white powder.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.06 (t, J=1.4 Hz, 1H),7.67-7.62 (m, 1H), 7.54 (dd, J=2.5, 1.4 Hz, 1H), 7.52 (d, J=1.1 Hz, 1H),5.84 (s, 2H), 3.93 (s, 3H), 2.53 (d, J=1.1 Hz, 3H).

Intermediate 3A Methyl 3-(5-ethyl-1,3-thiazol-2-yl)-5-hydroxybenzoate

A mixture of Intermediate 2 (7.08 g, 25.5 mmol),2-chloro-5-ethyl-1,3-thiazole (4.51 g, 30.5 mmol),[1,1,-Bis-(diphenylphosphino)-ferrocen]-palladium(II) dichloride (3.12g, 3.82 mmol), and K₂CO₃ (31 ml, 2.0 M, 61 mmol) in THF (420 mL) wasstirred at reflux until complete conversion. The solvent was evaporatedunder reduced pressure, water added and the mixture extracted withEtOAc. The combined organic layers were washed with saturated aqueousNaCl-solution and evaporated to dryness under reduced pressure. Crudematerial was purified by column chromatography (silica gel, hexane/EtOAcgradient) to give 2.54 g (38% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.26-1.32 (m, 3 H) 2.89 (m, 2 H) 3.87(s, 3 H) 7.39 (dd, 1 H) 7.52 (dd, 1 H) 7.66 (t, 1 H) 7.87 (t, 1 H) 10.24(s, 1 H).

Intermediate 3B Methyl 3-(5-chloro-1,3-thiazol-2-yl)-5-hydroxybenzoate

A mixture of Intermediate 2 (30.1 g, 50% purity, 54.2 mmol),2-bromo-5-chloro-1,3-thiazole (14.0 g, 70.4 mmol),[1,1,-Bis-(diphenylphosphino)-ferrocen]-palladium(II) dichloride (6.63g, 8.13 mmol), and K₂CO₃ (65 mL, 2.0 M, 130 mmol) in THF (890 mL) wasstirred at reflux until complete conversion. The solvent was evaporatedunder reduced pressure, water added and the mixture extracted withEtOAc. The combined organic layers were washed with saturated aqueousNaCl-solution and evaporated to dryness under reduced pressure. Crudematerial was purified by column chromatography (silica gel, hexane/EtOAcgradient) to give 5.21 g (34% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 3.85-3.90 (m, 3 H) 7.44 (dd, 1 H)7.51 (dd, 1 H) 7.84 (t, 1 H) 7.99 (s, 1 H) 10.35 (br. s., 1 H).

Intermediate 4A Methyl3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 3 (500 mg, 2.0 mmol), (bromomethyl)cyclopropane (331 uL,3.41 mmol) and potassium carbonate (554 mg, 4.01 mmol) were stirred inacetonitrile at 100° C. for 4 h. The reaction was re-treated with(bromomethyl)cyclopropane (331 uL, 3.41 mmol) and stirred at 100° C. fora further 4 h. The reaction mixture was filtered and the filtrateconcentrated under vacuum. Crude material was purified by BiotageIsolera™ chromatography (eluting with 1-40% EtOAc in heptane on a 50 gpre-packed HP-SiO₂ column) to give the title compound 498.4 mg (74%yield) as a pale yellow semi-crystalline solid.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.10 (t, J=1.4 Hz, 1H),7.73-7.64 (m, 1H), 7.59 (dd, J=2.5, 1.4 Hz, 1H), 7.51 (d, J=1.1 Hz, 1H),3.92 (d, J=6.9 Hz, 5H), 2.52 (d, J=1.1 Hz, 3H), 1.35-1.26 (m, 1H),0.73-0.60 (m, 2H), 0.38 (q, J=4.7 Hz, 2H).

LCMS (Analytical Method A): Rt=1.48 min, MS (ESIpos): m/z=304 (M+H)⁺.

Intermediate 5A3-(Cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 4A (498.4 mg, 1.48 mMol) was dissolved in MeOH (5 mL) andTHF (5 mL). 1M LiOH (2.2 mL) was added, and the reaction stirred at RTfor 2 h. Further 1M LiOH (1 mL) was added and the reaction stirred for 1h. The reaction mixture was concentrated to dryness and the residuetaken up in water (5 mL) and washed with EtOAc (2×5 mL). The aqueouslayer was acidified to pH 4 with 1M HCl and extracted with DCM (4×10mL). The combined organics were dried (MgSO₄), filtered and concentratedto give the title compound 389.5 mg (91% yield) as a white powder.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.27 (s, 1H), 7.68 (d, J=1.5 Hz,1H), 7.65 (d, J=1.3 Hz, 1H), 7.57 (d, J=1.1 Hz, 1H), 3.94 (d, J=6.9 Hz,2H), 2.54 (d, J=1.0 Hz, 3H), 1.28 (d, J=14.7 Hz, 1H), 0.68 (q, J=6.1 Hz,2H), 0.39 (q, J=4.8 Hz, 2H).

LC-MS (Analytical Method A) Rt=1.32 min, MS (ESIpos): m/z=290 (M+H)⁺.

Intermediate 6B (3S)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate

A solution of (3S)-tetrahydrofuran-3-ol (23.6.0 g, 268 mmol), TEA (56ml, 402 mmol) and trimethylamine hydrochloride (2.6 g, 27 mmol) werestirred in DCM (500 mL) and cooled to 0° C. 4-Methylbenzenesulfonylchloride (63.8 g, 335 mmol) was added portionwise and the mixturestirred at RT for 4 h. TLC (50% EtOAc in heptane) indicated completeconsumption of alcohol. Excess 4-methylbenzenesulfonyl chloride wasreacted with N,N-dimethylethane-1,2-diamine (8.8 ml, 80 mmol). The crudereaction mixture was washed with 1 M HCl (2×500 mL) and the organicportion dried (MgSO₄), filtered and concentrated under reduced pressureto give the title compound 64.6 g (99% yield) of as orange viscous oil.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.79 (d, J=8.3 Hz, 2H), 7.35 (d,J=8.0 Hz, 2H), 5.11 (tt, J=4.7, 2.3 Hz, 1H), 3.91-3.78 (m, 4H), 2.45 (s,3H), 2.12-2.07 (m, 2H).

Intermediate 7 Methyl 3-bromo-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

A mixture of Intermediate 1 (15 g, 4.33 mmol), Intermediate 6B (20.4 g,84.4 mmol) and cesium carbonate (42.3 g, 129.8 mmol) were stirred inacetonitrile (250 mL) at 100° C. overnight. The cooled reaction mixturewas filtered through celite, washed with EtOAc and the filtrateevaporated. The residue was dissolved in EtOAc (200 mL), washed withwater (2×200 mL), brine (100 mL), dried (MgSO₄), filtered andconcentrated at reduced pressure. Crude material was purified by BiotageIsolera™ chromatography (eluting with 1-50% EtOAc in heptane on a 340 gpre-packed HP-SiO₂ column) to give the title compound 18.12 g (92%yield) as colourless oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.77 (t, J=1.5 Hz, 1H), 7.44(dd, J=2.4, 1.3 Hz, 1H), 7.23-7.19 (m, 1H), 4.96 (ddt, J=6.2, 4.2, 2.0Hz, 1H), 4.06-3.86 (m, 7H), 2.33-2.19 (m, 1H), 2.18-2.05 (m, 1H).

Intermediate 8 Methyl3-[(3R)-tetrahydrofuran-3-yl]oxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Intermediate 7 (18.1 g, 59.8 mmol), bis(pinacolato)diborane (16.7 g,65.7 mmol) and potassium acetate (17.6 g, 179.3 mmol) were dissolved in1,4-dioxane (200 mL) and the solution degassed with a stream of nitrogenfor 10 min. Pd(dppf)Cl₂.CH₂Cl₂ (2.4 g, 2.99 mmol) was added and theresulting solution was degassed with a stream of nitrogen for a further10 min before the reaction mixture was stirred at 100° C. for 2 h. Thereaction mixture was cooled to RT then filtered through Celite® andconcentrated in vacuo to give a brown solid. The crude material waspurified by dry flash silica chromatography (eluting with 0-25% EtOAc inheptanes). The material was further purified by slurrying in heptane togive the title compound 16.57 g (80% yield) as an off-white solid.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.06 (d, J=1.0 Hz, 1H), 7.61(dd, J=2.7, 1.5 Hz, 1H), 7.54-7.45 (m, 1H), 5.03 (ddt, J=6.4, 4.4, 2.0Hz, 1H), 4.07-3.86 (m, 7H), 2.32-2.08 (m, 2H), 1.34 (s, 12H).

Intermediate 4B Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

Intermediate 8 (5.2 g, 14.9 mmol), 2-bromo-5-methyl-1,3-thiazole (1.87mL, 17.9 mmol) and cesium carbonate (12.2 g, 37.3 mmol) were dissolvedin 4:1 1,4-dioxane/water (75 mL). The solution was degassed with astream of nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0)(517.7 mg, 0.45 mmol) was added and the reaction mixture heated at 100°C. overnight. The reaction mixture was diluted with water (100 mL) andextracted with DCM (2×100 mL). The combined organics were dried (MgSO₄),filtered and concentrated under reduced pressure. The crude material waspurified by Biotage Isolera™ chromatography (eluting with 1-40% EtOAc inheptane on a 100 g KP-SiO2 column) to give the title compound 3.06 g(64% yield) as a yellow solid.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.11 (t, J=1.4 Hz, 1H),7.67-7.63 (m, 1H), 7.55 (dd, J=2.5, 1.4 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H),5.07 (td, J=4.1, 2.2 Hz, 1H), 4.11-3.86 (m, 7H), 2.53 (d, J=1.1 Hz, 3H),2.35-2.09 (m, 2H).

LCMS (Analytical Method A) Rt=1.34 min, MS (ESIpos): m/z=320 (M+H)⁺.

Intermediate 5B3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid

In analogy to Intermediate 5A, reaction of 8 g (25.0 mmol) Intermediate4B with 1M lithium hydroxide (20 mL) gave title compound 5.83 g (76%yield) as white powder.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.30 (s, 1H), 7.69-7.56 (m, 3H),5.08 (s, 1H), 4.12-3.87 (m, 4H), 2.54 (s, 3H), 2.39-2.11 (m, 2H).

LCMS (Analytical Method A) Rt=1.16 min, MS (ESIpos): m/z=305.9 (M+H)⁺.

Intermediate 6C (3R)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate

A solution of (3R)-tetrahydrofuran-3-ol (18.0 g, 204 mmol), TEA (43 mL,306 mmol) and trimethylamine hydrochloride (1.95 g, 20 mmol) werestirred in DCM (625 mL) at RT. 4-Methylbenzenesulfonyl chloride (42.8 g,2255 mmol) was added and the mixture stirred at RT for 20 h. Excess4-methylbenzenesulfonyl chloride was reacted withN,N-dimethylethane-1,2-diamine (26 ml, 245 mmol). Water was added andthe crude reaction mixture was extracted three times with DCM. Thecombined organic portions were concentrated under reduced pressure andpurified via column chromatography (silica gel, hexane/EE gradient) togive 41 g (83% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.83-1.94 (m, 1 H) 2.08 (dtd, J=14.29,8.32, 8.32, 6.08 Hz, 1 H) 2.43 (s, 3 H) 3.61-3.80 (m, 4 H) 5.12 (ddt,J=5.83, 3.87, 1.62, 1.62 Hz, 1 H) 7.49 (d, J=8.11 Hz, 2 H) 7.81 (d,J=8.36 Hz, 2 H).

Intermediate 4C Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

Intermediate 3 (4.5 g, 18.2 mmol), Intermediate 6C (5.3 g, 21.8 mmol)and caesium carbonate (8.9 g, 27.3 mmol) were stirred in DMF (100 mL) at90° C. for 36 h. The reaction mixture was filtered and the filtrateconcentrated under reduced pressure. Crude material was purified bycolumn chromatography (silica gel, hexane/EE gradient) to give 3.9 g(67% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.96-2.05 (m, 1 H) 2.20-2.31 (m, 1 H)3.74-3.82 (m, 1 H) 3.82-3.94 (m, 6 H) 5.19-5.26 (m, 1 H) 7.48 (dd,J=2.41, 1.39 Hz, 1 H) 7.61 (dd, J=2.28, 1.52 Hz, 1 H) 7.66 (d, J=1.27Hz, 1 H) 8.00 (t, J=1.39 Hz, 1 H).

Intermediate 5C3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid

Intermediate 4C (3.9 g, 12.2 mmol) was dissolved in MeOH (200 mL). 2MNaOH (30.5 mL) was added, and the reaction stirred at RT for 3 days. Thereaction mixture was neutralized with 2N HCl, the aqueous phaseextracted with DCM and the combined organics concentrated to drynessunder reduced pressure to give 2.3 g (62% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.95-2.05 (m, 1 H) 2.19-2.30 (m, 1 H)3.73-3.94 (m, 4 H) 5.20 (dd, J=5.96, 4.44 Hz, 1 H) 7.46 (dd, J=2.41,1.39 Hz, 1 H) 7.58 (dd, J=2.41, 1.65 Hz, 1 H) 7.65 (d, J=1.27 Hz, 1 H)7.98 (t, J=1.39 Hz, 1 H) 13.06-13.46 (m, 1 H).

Intermediate 4D:3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzoate

To a solution of Intermediate 3 (300 mg, 1.203 mmol) in acetone (15 mL)was added K₂CO₃ (831.6 mg, 6.017 mmol) and 3-bromoprop-1-yne (201.1 μL,1.805 mmol). The reaction mixture was stirred for 2 h under reflux thencooled to RT and evaporated to dryness. Crude material was taken up inDCM and washed with 1M NaOH (aq) and brine. The organic phase wasevaporated to dryness to give a dark tan powder 489 mg (>100% yield).Purification by Biotage Isolera™ chromatography (on a pre-packed 10 gsilica column eluting with EtOAC/heptanes 0-100%) gave the titlecompound 335 mg (97% yield) as a pale yellow powder.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.16 (t, J=1.4 Hz, 1H), 7.74(dd, J=2.5, 1.6 Hz, 1H), 7.66 (dd, J=2.6, 1.4 Hz, 1H), 7.53 (d, J=1.2Hz, 1H), 4.80 (d, J=2.4 Hz, 2H), 3.94 (s, 3H), 2.55 (t, J=2.4 Hz, 1H),2.53 (d, J=1.1 Hz, 3H).

Intermediate 5D:3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzoic acid

In analogy to Intermediate 5A, reaction of 300 mg (0.625 mmol)Intermediate 4D with 1M lithium hydroxide (0.9 mL) gave 159 mg (89%yield) of the title compound.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 8.07-7.94 (m, 1H), 7.74-7.60 (m, 2H),7.56 (dd, J=2.4, 1.3 Hz, 1H), 4.96 (d, J=2.3 Hz, 2H), 3.63 (t, J=2.3 Hz,1H), 2.50 (s, 3H).

Intermediate 4E Methyl3-(but-2-yn-1-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

To a solution of Intermediate 3 (250 mg, 1.0 mmol) dissolved in acetone(10 mL) was added K₂CO₃ (693 mg, 5.0 mmol) and 1-bromo-2-butyne (175.4μL, 2.0 mmol) and the reaction mixture stirred for 2 h at 60° C. in asealed tube. The reaction mixture was cooled to RT, filtered andevaporated to dryness. The residue was taken up in DCM and washed withwater. The organic phase was dried (over MgSO₄) and evaporated atreduced pressure to give 300.9 mg (98% yield) of the title compound as atan powder.

¹H NMR (250 MHz, CDCl₃) δ [ppm] 8.15 (t, J=1.4 Hz, 1H), 7.74-7.70 (m,1H), 7.65 (dd, J=2.5, 1.4 Hz, 1H), 7.54-7.50 (m, 1H), 4.75 (q, J=2.3 Hz,2H), 3.94 (s, 3H), 2.53 (d, J=1.1 Hz, 3H), 1.87 (t, J=2.3 Hz, 3H).

LCMS (Analytical method A) Rt=1.43 min, MS (ESIpos): m/z=302 (M+H)+.

Intermediate 5E3-(But-2-yn-1-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of Intermediate 4E (300 mg, 1.00 mmol) in MeOH (5 mL) andTHF (5 mL) was added 1 M LiOH (2 mL) and the reaction stirred at RT for2 h. The reaction mixture was concentrated and the residue taken up inwater (5 mL) and washed with EtOAc (5 mL). The aqueous layer wasacidified to pH 4 with 1 M HCl and the precipitate collected by vacuumfiltration and dried in the vacuum oven to give 245.1 mg (85% yield) ofthe title compound as a white powder.

¹H NMR (250 MHz, DMSO-d6): δ 8.00 (t, J=1.4 Hz, 1H), 7.65 (q, J=1.4 Hz,2H), 7.54 (dd, J=2.5, 1.3 Hz, 1H), 4.89 (d, J=2.4 Hz, 2H), 1.84 (t,J=2.3 Hz, 3H).

Intermediate 4F Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzoate

Intermediate 3 (300 mg, 1.2 mmol), oxetan-3-yl tosylate (357 mg, 1.56mmol) and cesium carbonate (588 mg, 1.81 mmol) were combined inacetonitrile (5 mL) and stirred at 100° C. in a sealed tube for 6 h,then at 110° C. for 4 h. The reaction mixture was cooled to RT andfiltered through celite, washing with EtOAc. The filtrate wasconcentrated under reduced pressure and purified by Biotage Isolera™chromatography (silica gel eluting with heptanes-ethyl acetate 9:1 to2:3) to give 163.5 mg (43% yield) of the title compound as a colourlessgum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.12 (t, J=1.4 Hz, 1H), 7.52 (d,J=1.1 Hz, 1H), 7.51 (dd, J=2.5, 1.6 Hz, 1H), 7.37 (dd, J=2.5, 1.3 Hz,1H), 5.33 (p, J=5.6 Hz, 1H), 5.07-4.98 (m, 2H), 4.78 (dd, J=7.9, 5.1 Hz,2H), 3.94 (s, 3H), 2.53 (d, J=1.1 Hz, 3H).

LCMS (Analytical Method A) Rt=1.29 min, MS (ESIpos): m/z=309.95 (M+H)⁺.

Intermediate 5F 3-(5-Methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzoicacid

Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzoate (163.5mg, 0.52 mmol) was stirred in 1M LiOH (1 mL), THF (2 mL) and MeOH (2 mL)for 1 h. The organics were removed under reduced pressure and theresidue taken up in water (5 mL) and acidified to pH 3 with 1 M HCl. Theresulting precipitate was collected by vacuum filtration to give 151.8mg (100% yield) of the title compound as a white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.31 (t, J=1.4 Hz, 1H), 7.59 (d,J=1.1 Hz, 1H), 7.53 (dd, J=2.4, 1.7 Hz, 1H), 7.42 (dd, J=2.4, 1.3 Hz,1H), 5.35 (p, J=5.6 Hz, 1H), 5.05 (t, J=6.9 Hz, 2H), 4.80 (dd, J=7.7,5.1 Hz, 2H), 2.54 (d, J=1.0 Hz, 3H).

LCMS (Analytical Method A) Rt=1.12 min, MS (ESIpos): m/z=219.95 (M+H)⁺.

Intermediate 4G Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate

To a solution of Intermediate 3 (500 mg, 2.0 mmol),(2S)-tetrahydrofuran-2-ylmethanol (245 mg, 2.4 mmol) and PPh₃ (789 mg,3.0 mmol) in DCM (20 mL) was added DIAD (0.6 mL, 3.0 mmol) and theresulting solution stirred for 18 h at RT. The reaction mixture wasconcentrated and purified by Biotage Isolera™ chromatography (silicagel, eluting with 20-60% EtOAc in heptanes) to give 550 mg (50% yield)of the title compound as a colourless gum.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.11 (t, J=1.4 Hz, 1H), 7.70 (dd,J=2.5, 1.6 Hz, 1H), 7.61 (dd, J=2.5, 1.4 Hz, 1H), 7.51 (d, J=1.2 Hz,1H), 4.36-4.23 (m, 1H), 4.12-4.03 (m, 2H), 3.99-3.91 (m, 4H), 3.88-3.81(m, 1H), 2.52 (d, J=1.1 Hz, 3H), 2.13-2.05 (m, 1H), 2.03-1.89 (m, 2H),1.84-1.74 (m, 1H).

LCMS (Analytical Method F): Rt=3.64 min, MS (ESIpos); m/z=33 (M+H)+.

Intermediate 5G3-(5-Methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid

A mixture of methyl3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate(600 mg, 1.83 mmol) and 1M LiOH (10 mL, 10 mmol) in THF (20 mL) wasstirred at RT for 18 h. The reaction was neutralised with 1M HCl (10 mL)at 0° C., prior to addition of 10 mL buffer (pH=6.5). The aqueous phasewas extracted with CHCl₃/iPrOH (1:1, 4×5 mL) and the combined organiclayer dried (over Na₂SO₄) and concentrated at reduced pressure. Thecrude material was purified by Biotage Isolera™ chromatography (silicagel, eluting with 50% EtOAc in heptane and then 10% MeOH in DCM) to give520 mg (84% yield) of the title compound as a yellow gum.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.24 (s, 1H), 7.67 (s, 2H), 7.54 (s,1H), 4.31 (s, 1H), 4.15-3.77 (m, 4H), 2.50 (s, 3H), 2.13-1.66 (m, 4H).

LCMS (Analytical Method A): Rt=1.22 min, MS (ESIpos); m/z=391 (M+H)⁺.

Intermediate 4H Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate

To a suspension of Intermediate 3 (600 mg, 2.4 mmol) in DCM (10 mL) wasadded (2R)-tetrahydrofuran-2-ylmethanol (295 mg, 2.9 mmol) andtriphenylphosphine (950 mg, 3.6 mmol). DIAD (0.7 mL, 3.6 mmol) was addedat ˜10° C. and the resulting solution stirred at RT for 20 hours. Thereaction mixture was concentrated and the residue dissolved in THF (10mL) and retreated with (2R)-tetrahydrofuran-2-ylmethanol (150 mg, 1.4mmol), triphenylphosphine (475 mg, 1.8 mmol), DIAD (0.7 mL, 3.6 mmol)and the resulting solution stirred at RT for 72 hours. The reactionmixture was concentrated under reduced pressure and the residuepartitioned between water (20 mL) and EtOAc (20 mL). The aqueous layerwas re-extracted with EtOAc (2×20 mL) and the combined organics dried(over MgSO₄) and concentrated under reduced pressure. The crude materialwas purified by Biotage Isolera™ chromatography (eluting with 12-100%EtOAc in heptane on a 55 g pre-packed KP-NH SiO₂ column) to give 973 mg(55% yield) of the title compound.

¹H NMR (250 MHz, CDCl₃): δ [ppm] 8.11 (t, J=1.4 Hz, 1H), 7.76-7.67 (m,1H), 7.66-7.58 (m, 1H), 7.52 (d, J=1.1 Hz, 1H), 4.37-4.25 (m, 1H),4.19-4.04 (m, 3H), 3.93 (s, 4H), 3.91-3.81 (m, 2H), 3.80-3.67 (m, 2H),2.52 (d, J=1.0 Hz, 3H).

LCMS (Analytical Method A) Rt=1.39, MS (ESIpos): m/z=334.1 (M+H)+.

Intermediate 5H3-(5-Methyl-1,3-thiazol-2-yl)-5-[[(2R)-tetrahydrofuran-2-yl]methoxy]benzoicacid

To a solution of methyl3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate(973. mg, ˜45% purity, 1.31 mmol) in THF (1.8 mL) and methanol (1.3 mL)was added 1M LiOH (1.84 mL, 1.84 mmol) and the solution stirred at RTfor 2 h. The reaction mixture was concentrated under reduced pressure toremove organic solvents, diluted with 1M NaOH (13 mL) and washed withethyl acetate (2×20 mL). The aqueous phase was acidified to pH 4 with 1MHCl and the resulting precipitate collected by filtration, washed withwater and dried in the vacuum oven to give 258 mg (61% yield) of thetitle compound as a white powder.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 13.27 (s, 0.5H), 8.05-7.91 (m, 1H),7.69-7.63 (m, 1H), 7.63-7.57 (m, 1H), 7.54-7.43 (m, 1H), 4.24-4.15 (m,1H), 4.15-4.07 (m, 1H), 4.07-3.99 (m, 1H), 3.83-3.76 (m, 1H), 3.72-3.66(m, 1H), 2.51 (s, 3H), 2.07-1.96 (m, 1H), 1.96-1.77 (m, 2H), 1.77-1.64(m, 1H).

LCMS (Analytical Method A) Rt=1.24 min, MS (ESIpos): m/z=320 (M+H)⁺.

Intermediate 4I Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

To a suspension of Intermediate 3 (300 mg, 1.2 mmol),(3R)-tetrahydrofuran-3-ylmethanol (185 mg, 1.8 mmol) andtriphenylphosphine (475 mg, 1.8 mmol) in DCM (10 mL) was added DIAD (355μl, 1.8 mmol) and the resulting solution was stirred over the weekend(˜65 hours) at RT. The reaction mixture was washed with water (20 mL)and the aqueous layer re-extracted with DCM (2×20 mL). The combinedorganics were dried (over MgSO₄) and concentrated under reduced. Thecrude material was purified by Biotage Isolera™ chromatography (silicagel, eluting with heptanes-EtOAc, 1:0 to 35:65) to give 700 mg (91%yield) of the title compound.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.09 (t, J=1.4 Hz, 1H),7.71-7.67 (m, 1H), 7.58 (dd, J=2.5, 1.4 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H),4.05 (dd, J=8.9, 6.5 Hz, 1H), 4.02-3.97 (m, 1H), 3.94 (s, 3H), 3.96-3.88(m, 5H), 3.83-3.77 (m, 1H), 3.72 (dd, J=8.9, 5.3 Hz, 1H), 2.77 (hept,J=6.8, 6.2 Hz, 1H), 2.53 (d, J=1.1 Hz, 3H), 2.13 (dtd, J=13.5, 8.1, 5.6Hz, 1H), 1.76 (td, J=12.7, 6.9 Hz, 1H).

Intermediate 5I3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoicacid

To a solution of methyl3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate(939 mg, 1.41 mmol, ˜50% purity) in THF (3 mL) was added 1M aqueoussodium hydroxide (3 mL). The reaction was stirred vigorously for 18 h atRT, an additional portion of 1M aqueous sodium hydroxide (1 mL) wasadded and the reaction was stirred vigorously for 4 h at RT. Thereaction mixture was acidified to pH 3 with 1M HCl and extracted intoEtOAc (3×30 mL) and the combined organics washed with 1M HCl (4×20 mL).The aqueous phase was concentrated (to ˜20 mL) and extracted with DCM(4×20 mL). The combined DCM and EtOAc organics were dried (over MgSO₄)and concentrated to give 600 mg (86% yield) of the title compound.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.22 (t, J=1.4 Hz, 1H), 7.84 (s,1H), 7.69 (dd, J=2.4, 1.3 Hz, 1H), 7.66-7.62 (m, 1H), 4.17-4.02 (m, 2H),4.01-3.91 (m, 2H), 3.87-3.74 (m, 0H), 2.86-2.75 (m, 1H), 2.58 (d, J=0.8Hz, 0H), 2.23-2.12 (m, 2H), 2.07 (s, 1H), 1.86-1.76 (m, 1H).

LCMS (Analytical Method A) R_(t)=1.20 min, MS (ESIpos) m/z=320 (M+H)⁺.

Intermediate 4J: Methyl3-(5-Methyl-1,3-thiazol-2-yl)-5-[[(3R)-tetrahydrofuran-3-yl]methoxy]benzoate

To a stirred solution of PPh₃ (552 mg, 2.11 mmol) and DIAD (415 μL, 2.11mmol) in THF (8 mL) was added Intermediate 3 (350 mg, 1.40 mmol) and(3S)-tetrahydrofuran-3-ylmethanol (215 mg, 2.11 mmol). The reactionmixture was stirred at RT for 16 h then concentrated in vacuo. Theresidue was taken up in DCM and washed with water, dried (over Na₂SO₄)and concentrated in vacuo to give an amber viscous oil. The crudematerial was purified by Biotage Isolera™ chromatography (on KP-NHsilica gel, eluting with heptanes-DCM, 1:0 to 7:3) to give 566 mg (40%yield) of the title compound as an off white gum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.08 (s, 1H), 7.71-7.63 (m, 5H),7.60-7.50 (m, 4H), 7.46 (td, J=7.7, 2.8 Hz, 4H), 4.07-3.87 (m, 7H), 3.79(q, J=7.7 Hz, 1H), 3.72 (dd, J=8.9, 5.3 Hz, 1H), 2.83-2.70 (m, J=7.2,6.4 Hz, 1H), 2.52 (s, 3H), 2.13 (dtd, J=13.6, 8.1, 5.6 Hz, 1H), 1.76(dq, J=12.9, 7.1 Hz, 1H), 1.36-1.17 (m, 3H), 0.87 (t, J=7.0 Hz, 1H).

LCMS (Analytical Method A) R_(t)=1.37 min, MS (ESIpos) m/z=334 (M+H)⁺.

Intermediate 5J3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoicacid

To a solution of methyl3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoate(566 mg, 0.80 mmol, ˜50% purity) in THF (1.2 mL) and methanol (0.5 mL)was added aqueous 1M lithium hydroxide (1.2 mL) and the reaction mixturestirred at RT for 2 h. The reaction mixture was diluted with water (3mL) and washed with EtOAc (2×6 mL). The aqueous phase was acidified topH ˜4 leading to precipitation of a white solid. Filtration gave 264 mg(98% yield) of the title compound as a white solid.

LCMS (Analytical Method A) R_(t)=1.20 min, MS (ESIpos) m/z=320 (M+H)⁺.

Intermediate 4K Methyl3-(5-Methyl-1,3-thiazol-2-yl)-5-tetrahydro-2H-pyran-4-yloxy-benzoate

To a solution of Intermediate 3 (700 mg, 2.81 mmol),tetrahydro-2H-pyran-4-ol (0.386 mL, 3.65 mmol) and triphenylphosphine(957 mg, 3.65 mmol) in THF (10 mL) was slowly added DIAD (0.724 mL, 3.65mmol) and the reaction mixture stirred at RT for 19 h. The reactionmixture was diluted with water (20 mL) and extracted with EtOAc (2×30mL). The combined organic phases were washed with brine (10 mL), dried(over Na₂SO₄) and concentrated in vacuo. The resulting material waspurified by chromatography using silica gel (gradient: hexane/EE) togive 571 mg (54% yield) of the title compound as a yellow oil. Theimpure fractions from chromatography were re-purified using the sameconditions to give an additional 981 mg (25% yield) of title compound.

¹H NMR (500 MHz, CDCl₃): δ 8.11-8.06 (m, 1H), 7.72-7.68 (m, 1H),7.60-7.58 (m, 1H), 7.53-7.48 (m, 1H), 4.69-4.60 (m, 1H), 4.02-3.96 (m,2H), 3.94 (s, 3H), 3.66-3.57 (m, 2H), 2.53 (d, J=1.1 Hz, 3H), 2.10-2.00(m, 2H), 1.87-1.77 (m, 2H).

Intermediate 5K3-(5-Methyl-1,3-thiazol-2-yl)-5-tetrahydro-2H-pyran-4-yloxy-benzoic acid

To a solution of methyl3-(5-Methyl-1,3-thiazol-2-yl)-5-tetrahydro-2H-pyran-4-yloxy-benzoate(565 mg, 1.49 mmol) in THF/MeOH (1:1, 6 mL) was added 1M LiOH (2.24 mL,2.24 mmol) and the reaction mixture stirred at RT for 3 h. The reactionmixture was adjusted to pH-3 with 1 M HCl then extracted with EtOAc(2×15 mL). Combined organic phases were washed with brine (5 mL), dried(using Biotage phase separator) and concentrated in vacuo to give 516 mg(90% yield) of the title compound as an off-white solid.

¹H NMR (250 MHz, CDCl₃): δ [ppm] 8.36-8.21 (m, 1H), 7.73-7.63 (m, 2H),7.61-7.57 (m, 1H), 4.75-4.58 (m, 1H), 4.08-3.94 (m, 2H), 3.71-3.54 (m,2H), 2.54 (d, J=1.1 Hz, 3H), 2.17-1.99 (m, 2H), 1.94-1.73 (m, 2H).

LCMS (Analytical Method A) Rt=1.16 min, MS (ESIpos): m/z=320 (M+H)+.

Intermediate 4L Methyl3-(5-Methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

To a stirred solution of Intermediate 3 (250 mg, 1 mmol) and4-(bromomethyl)tetrahydro-2H-pyran (449 mg, 2.51 mmol) in anhydrous MeCN(7 mL) was added dipotassium carbonate (347 mg, 2.51 mmol). The reactionmixture was stirred overnight at 100° C., cooled to RT, filtered throughCelite® and concentrated under reduced pressure. The resulting materialwas purified by chromatography using silica gel (gradient: hexane/EE) togive 1.0 g (76% yield) of the title compound as a colourless oil.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.08 (t, J=1.4 Hz, 1H), 7.69-7.67 (m,1H), 7.57 (dd, J=2.5, 1.4 Hz, 1H), 7.53-7.51 (m, 1H), 4.05-4.00 (m, 2H),3.94 (s, 3H), 3.92 (d, J=6.5 Hz, 2H), 3.49-3.42 (m, 2H), 2.53-2.52 (m,3H), 2.14-2.03 (m, 1H), 1.80-1.75 (m, 2H), 1.53-1.43 (m, 2H).

LCMS (Analytical Method A) Rt=1.45 min, MS (ESIpos): m/z=348 (M+H)⁺.

Intermediate 5L3-(5-Methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoicacid

To a solution of methyl3-(5-Methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate(1 g, 2.88 mmol) in THF (6 mL) and MeOH (6 mL) was added 1M LiOH (4.3mL) at RT and the resulting solution stirred overnight at RT. Thereaction mixture was concentrated under reduced pressure, the residuetaken up in water and acidified to pH 4 with 1M HCl resulting inprecipitate formation. The precipitate was collected by vacuumfiltration, washed with ethyl acetate and vacuum dried to give 179 mg(16% yield) of the title as a white solid. The filtrate was re-extractedwith IPA/Chloroform 50:50, the combined organic layers washed with brineand dried (over Na₂SO₄) and concentrated to give 302 mg (27% yield) of asecond batch of the title compound as a white solid.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 7.97 (s, 1H), 7.66-7.64 (m, 1H),7.62-7.60 (m, 1H), 7.50 (s, 1H), 3.97 (d, J=6.4 Hz, 2H), 3.92-3.86 (m,2H), 3.38-3.34 (m, 2H), 2.54-2.49 (m, 3H), 2.10-1.99 (m, 1H), 1.75-1.68(m, 2H), 1.42-1.32 (m, 2H)

LCMS (Analytical Method A) Rt=1.24 min, MS (ESIpos): m/z=334 (M+H)⁺.

Intermediate 5M3-(5-methyl-1,3-thiazol-2-yl)-5-[(2-methylpyridin-4-yl)oxy]benzoic acid

A mixture of Intermediate 3 (1.0 g, 3.81 mmol),4-fluoro-2-methylpyridine (0.63 g, 5.71 mmol) and Cs₂CO₃ (2.48 g, 7.6mmol) in DMSO (10 mL) was heated at 100° C. for 6 h. The reactionmixture was treated with 1 M aqueous NaOH (5 mL) and stirred for 30 min.The solution was diluted with water (30 mL) and acidified to pH 4 with1M aqueous HCl. On addition of EtOAc (40 mL) a precipitate formed thatwas collected by vacuum filtration to give 722 mg (56% yield) of thetitle compound as an orange powder.

¹H NMR (500 MHz, MeOH-d4): δ [ppm]=8.39 (t, J=1.5 Hz, 1H), 8.35 (d,J=6.0 Hz, 1H), 7.90-7.85 (m, 1H), 7.77 (dd, J=2.3, 1.4 Hz, 1H), 7.58 (d,J=1.2 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.93 (dd, J=6.0, 2.5 Hz, 1H),2.55 (d, J=1.1 Hz, 3H), 2.52 (s, 3H).

LCMS (Analytical Method A) Rt=0.96 min, MS (ESIpos) m/z=327 (M+H)⁺.

Intermediate 9 Methyl 3,5-dibromobenzoate

A solution of 3,5-dibromobenzoic acid (10.5 g, 37.5 mmol) and acetylchloride (6.7 mL, 93.8 mmol) in methanol (212 mL) was stirred underreflux for 17 h. The solvent was removed under reduced pressure. Thecrude material was purified by column chromatography (silica gel,hexane/EE gradient) to give the title compound 11.0 g (99% yield).

Intermediate 10 Methyl 3-bromo-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 9 (3.5 g, 11.91 mmol) and5-methyl-2-(tributylstannanyl)-1,3-thiazole (4.62 g, 11.91 mmol) weredissolved in DMF (105 mL). The solution was degassed with a stream ofnitrogen for 10 minutes, tetrakis(triphenylphosphine)palladium(0) (550mg, 0.476 mmol) was added and the reaction mixture heated at 100° C. for17 hours. The reaction mixture was concentrated under reduced pressure.Crude material was purified by column chromatography (silica gel,hexane/EE gradient) to afford the title compound 1.72 g (42% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 2.53 (d, J=1.27 Hz, 3 H) 3.89-3.94 (m,3 H) 7.71 (d, J=1.27 Hz, 1 H) 8.08-8.11 (m, 1 H) 8.27 (t, J=1.77 Hz, 1H) 8.35 (t, J=1.52 Hz, 1 H).

Intermediate 5N3-[(6-Methylpyridin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 10 (1.29 g, 4.14 mmol), 5-hydroxy-2-methylpyridine (903 mg,8.28 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (0.11 ml, 0.83 mmol),Cu(I)Cl (165 mg, 1.65 mmol) and Cs₂CO₃ (4.05 g, 12.4 mmol) in NMP (51mL) were stirred at 220° C. for 20 minutes using a microwave. Thereaction mixture was concentrated to dryness under reduced pressure andthe crude material purified by column chromatography (silica gel,hexane/EE gradient) to give 1.0 g (70% purity, 52% yield) of the titlecompound.

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 7.31 (d, 1 H) 7.45 (d, 1 H) 7.49 (m, 2H) 7.58 (d, 1 H) 8.08-8.16 (m, 1 H) 8.31 (d, 1 H).

Intermediate 4O Methyl3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A solution of Intermediate 3 (250 mg, 1.0 mmol),2-bromo-5-methyl-1,3,4-thiadiazole (270 mg, 1.5 mmol) and cesiumcarbonate (654 mg, 2.0 mmol) in DMF (5 mL) was heated in a sealed tubeat 110° C. overnight. The cooled reaction mixture was concentrated underreduced pressure and the residue partitioned between water (10 mL) andDCM (10 mL). The aqueous layer was extracted with DCM (10 mL) and thecombined organics dried (over MgSO₄) and concentrated under reducedpressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptanes-EtOAc, 4:1 to 3:7).Mixed fractions were re-purified by Biotage Isolera™ chromatography(eluting with heptanes-EtOAc, 1:0 to 3:7). Clean fractions from bothpurifications were combined and concentrated to give 204.9 mg (59%yield) of the title compound as an off-white solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.39 (t, J=1.4 Hz, 1H), 8.09(dd, J=2.3, 1.7 Hz, 1H), 7.98 (dd, J=2.4, 1.4 Hz, 1H), 7.54 (d, J=1.1Hz, 1H), 3.95 (s, 3H), 2.69 (s, 3H), 2.54 (d, J=1.0 Hz, 3H).

LCMS (Analytical Method A) Rt=1.33 min, MS (ESIpos) m/z=348 (M+H)⁺.

Intermediate 5O3-[(5-Methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a stirred solution of methyl3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate(204.9 mg, 0.59 mmol) in MeOH (2.5 mL) and THF (2.5 mL) was added 1MLiOH (2.5 mL). After 1 h the reaction mixture was concentrated underreduced pressure and the residue taken up in water (5 mL) and washedwith EtOAc (5 mL). The aqueous layer was acidified with 1M HCl to pH ˜3to form a white precipitate that was collected by vacuum filtration togive 128.6 mg (58% yield) of the title compound as a white powder.

¹H NMR (500 MHz, DMSO-d6): δ [ppm]=8.29 (s, 1H), 8.10 (s, 1H), 7.90 (s,1H), 7.69 (s, 1H), 2.64 (s, 3H), 2.52 (s, 3H).

LCMS (Analytical Method A) Rt=1.15 mins, MS (ESIpos) m/z=334 (M+H)⁺.

Intermediate 5P3-(5-methyl-1,3-thiazol-2-yl)-5-(1,3-thiazol-2-yloxy)benzoic acid

A solution of Intermediate 3 (250 mg, 1.0 mmol), 2-bromothiazole (246.7mg, 1.5 mmol) and cesium carbonate (654 mg, 2.0 mmol) in DMF (5 mL) washeated in a sealed tube at 110° C. overnight. The cooled reactionmixture was treated with 1M LiOH (2 mL) and stirred at 110° C. for 1 h.The reaction mixture was concentrated under reduced pressure and theresidue taken up in water (10 mL) and washed with EtOAc (2×10 mL). Theaqueous layer was acidified to pH 3 with 1 M HCl and the solutionextracted with DCM (3×10 mL). The combined organics were dried (overMgSO₄) and concentrated under reduced pressure to give 328.3 mg (86%yield) of the title compound as a brown powder.

¹H NMR (500 MHz, DMSO-d6): δ [ppm]=8.26 (d, J=1.3 Hz, 1H), 8.08-8.05 (m,1H), 7.86 (dd, J=2.2, 1.4 Hz, 1H), 7.69-7.67 (m, 1H), 7.36 (d, J=3.8 Hz,1H), 7.34 (d, J=3.8 Hz, 1H), 2.52 (s, 3H).

LCMS (Analytical Method A) Rt=1.23 min, MS (ESIpos) m/z=319 (M+H)⁺.

Intermediate 11 Methyl 3-bromo-5-(2-hydroxy-2-methylpropoxy)benzoate

A mixture of Intermediate 1 (1.92 g, 8.33 mmol), 2,2-dimethyloxirane (3g, 41.5 mmol) and K₂CO₃ (2.3 g, 16.6 mmol) in DMSO (23 mL) were stirredat 100° C. for 17 h. The reaction mixture was filtered, washed with DCM.The organics were washed with water and concentrated at reducedpressure. Crude material was purified by column chromatography (silicagel, hexane/EE gradient) to give the title compound 2.1 g (87% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.16-1.23 (m, 6 H) 3.80 (s, 2 H) 3.86(s, 3 H) 4.66 (s, 1 H) 7.41-7.49 (m, 2 H) 7.62 (t, J=1.52 Hz, 1 H).

Intermediate 12 3-Bromo-5-(2-methoxy-2-methylpropoxy)benzoic acid

637 mg NaH (60%, 15.9 mmol) were added to a solution of Intermediate 11(1.92 g, 6.64 mmol) in THF (21 mL) at RT and stirred for 30 minutesbefore adding methyl iodide (1.24 ml, 19.9 mmol) at RT. The reactionmixture stirred at 50° C. for 1 hour and at RT overnight. The reactionmixture was diluted with water and extracted three times with DCM. Theorganics were concentrated at reduced pressure to give the titlecompound (2.9 g, >100% yield) which was used without furtherpurification in the next step.

Intermediate 13 Methyl 3-bromo-5-(2-methoxy-2-methylpropoxy)benzoate

A mixture of crude Intermediate 12 (2.9 g) and acetyl chloride (1.7 ml,23.9 mmol) in MeOH (130 mL) were stirred at 90° C. The reaction mixturewas concentrated at reduced pressure. Crude material was purified bycolumn chromatography (silica gel, hexane/EE gradient) to give the titlecompound 1.66 g (79% yield over two steps from Intermediate 11).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.21 (s, 6 H) 3.15 (s, 3 H) 3.86 (s, 3H) 3.94 (s, 2 H) 7.45 (dd, J=2.40, 1.39 Hz, 1 H) 7.49 (t, J=2.15 Hz, 1H) 7.63 (t, J=1.52 Hz, 1 H).

Intermediate 14Q Methyl3-(2-methoxy-2-methylpropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of Intermediate 13 (1.66 g, 5.23 mmol),bis(pinacolato)diborane (3.32 g, 13.08 mmol), potassium acetate (1.8 g,18.3 mmol) and Pd(dppf)Cl₂ (383 mg, 0.52 mmol) in 1,4-dioxane (100 mL)was stirred at 90° C. for 17 hours. The reaction mixture was cooled toRT and concentrated in vacuo. The remaining crude reaction mixture wasextracted three times with DCM and concentrated in vacuo again. Crudematerial was purified by column chromatography (silica gel, hexane/EEgradient) to give the title compound 1.2 g (63% yield).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.22 (s, 6 H) 1.31 (s, 12 H) 3.16 (s,3 H) 3.86 (s, 3 H) 3.92 (s, 2 H) 7.41 (d, J=2.07 Hz, 1 H) 7.56 (dd,J=2.64, 1.70 Hz, 1 H) 7.85 (s, 1 H).

Intermediate 15Q Methyl3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)benzoate

Intermediate 14Q (1.15 g, 3.16 mmol), 2-bromo-5-chloro-1,3-thiazole (752mg, 3.79 mmol) and Pd(dppf)Cl₂ (347 mg, 0.47 mmol) were dissolved in 1MK₂CO₃ aqueous solution (7.58 mL) and THF (100 mL). The reaction mixturewas stirred at RT for 4 days and for another day at 90° C. The reactionmixture was concentrated under reduced pressure, the remaining materialdiluted with water and extracted three times with DCM. The combinedorganics were concentrated under reduced pressure. Crude material waspurified by column chromatography (silica gel, hexane/EE gradient) toafford the title compound 790 mg (70% yield).

Intermediate 5Q3-(5-Chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)benzoic acid

Intermediate 15Q (790 mg, 2.22 mmol) was dissolved in MeOH (40 mL). 2MNaOH (5.55 mL) was added, and the reaction stirred at RT overnight. Thereaction mixture was neutralized with 2N HCl, the aqueous phaseextracted with DCM and the combined organics concentrated to drynessunder reduced pressure to give 460 mg (56% yield) of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.22-1.25 (m, 6 H) 3.17 (s, 3 H) 3.99(s, 2 H) 7.57 (dd, J=2.45, 1.32 Hz, 1 H) 7.62-7.66 (m, 1 H) 7.96-8.02(m, 2 H) 13.22-13.43 (m, 1 H).

Intermediate 16 Methyl3-bromo-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

Intermediate 1 (5.1 g, 22.1 mmol), 4-(bromomethyl)tetrahydro-2H-pyran(4.35 g, 24.3 mmol) and caesium carbonate (36 g, 110 mmol) were stirredin DMF (150 mL) at 120° C. for 22 h. The reaction mixture was filteredand the filtrate concentrated under reduced pressure. Crude material(7.1 g) contained the title compound alongside with the correspondingcarboxylic acid.

This mixture was stirred in methanol (150 mL) and acetyl chloride (4.23g, 53.9 mmol) at 90° C. for 16 hours. The reaction mixture was filteredand the filtrate concentrated under reduced pressure. Crude material waspurified by column chromatography (silica gel, hexane/EE gradient) toafford the title compound 6.02 g (83% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.26-1.39 (m, 2 H) 1.66 (dd, J=12.80,1.90 Hz, 2 H) 1.94-2.06 (m, 1 H) 3.29-3.37 (m, 2 H) 3.85-3.90 (m, 5 H)3.92 (d, J=6.34 Hz, 2 H) 7.42 (dd, J=2.41, 1.39 Hz, 1 H) 7.46 (t, J=2.15Hz, 1 H) 7.62 (t, J=1.52 Hz, 1 H).

Intermediate 14 R: Methyl3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of Intermediate 16 (6.2 g, 18.8 mmol), bis(pinacolato)diborane(11.96 g, 47.1 mmol), potassium acetate (6.47 g, 65.9 mmol) andPd(dppf)Cl₂ (1.38 g, 1.88 mmol) in 1,4-dioxane (150 mL) was stirred at90° C. for 17 hours. The reaction mixture was cooled to RT andconcentrated in vacuo. The remaining crude reaction mixture was purifiedby column chromatography (silica gel, hexane/EE gradient) to give thetitle compound 9.2 g (quantitative yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.29-1.41 (m, 14 H) 1.64-1.72 (m, 2 H)1.93-2.06 (m, 1 H) 3.33 (d, J=1.52 Hz, 2 H) 3.84-3.94 (m, 7 H) 7.38 (dd,J=2.79, 0.76 Hz, 1 H) 7.53-7.55 (m, 1 H) 7.83-7.85 (m, 1 H).

Intermediate 15R Methyl3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-[5-(trifluoromethyl)-1,3-thiazol-2-yl]benzoate

Intermediate 14R (717 mg, 1.9 mmol),2-bromo-5-(trifluoromethyl)-1,3-thiazole (531 mg, 2.29 mmol) andPd(dppf)Cl₂ (209 mg, 0.29 mmol) were dissolved in 1M K₂CO₃ aqueoussolution (4.5 mL) and THF (30 mL). The reaction mixture was heated at120° C. for 90 minutes in the microwave. The reaction mixture wasconcentrated under reduced pressure, the remaining material diluted withwater and extracted three times with DCM. The combined organics wereconcentrated under reduced pressure. Crude material was purified bycolumn chromatography (silica gel, hexane/EE gradient) to afford thetitle compound in a mixture with unreacted boronic acid (300 mg).

Intermediate 5R:3-(Tetrahydro-2H-pyran-4-ylmethoxy)-5-[5-(trifluoromethyl)-1,3-thiazol-2-yl]benzoicacid

Intermediate 15R (300 mg, 0.75 mmol) was dissolved in MeOH (30 mL). 2MNaOH (1.87 mL) was added and the reaction stirred at RT. The reactionmixture was concentrated under reduced pressure, neutralized with 2NHCl, the aqueous phase extracted three times with DCM and the combinedorganics concentrated to dryness under reduced pressure to give 230 mgof the crude title compound (55% purity by LCMS), which was used withoutfurther purification.

Intermediate 15S Methyl3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

Intermediate 14R (667 mg, 1.77 mmol), 2-chloro-5-cyclobutyl-1,3-thiazole(369 mg, 2.13 mmol) and Pd(dppf)Cl₂ (194 mg, 0.27 mmol) were dissolvedin 1M K₂CO₃ aqueous solution (4.25 mL) and THF (28 mL). The reactionmixture was stirred at 90° C. overnight. The reaction mixture wasconcentrated under reduced pressure, the remaining material diluted withwater and extracted three times with DCM. The combined organics wereconcentrated under reduced pressure. Crude material was purified bycolumn chromatography (silica gel, hexane/EE gradient) to afford thetitle compound 180 mg (26% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.33-1.43 (m, 2 H) 1.70 (dd, J=12.67,1.77 Hz, 2 H) 1.85-1.95 (m, 1 H) 1.96-2.05 (m, 2 H) 2.15 (td, J=9.00,2.53 Hz, 2 H) 2.40-2.46 (m, 2 H) 3.33-3.39 (m, 2 H) 3.76-3.84 (m, 1 H)3.86-3.91 (m, 5 H) 3.97 (d, J=6.34 Hz, 2 H) 7.49 (dd, J=2.41, 1.39 Hz, 1H) 7.63 (dd, J=2.28, 1.52 Hz, 1 H) 7.69 (d, J=0.76 Hz, 1 H) 8.00 (t,J=1.52 Hz, 1 H).

Intermediate 5S3-(5-Cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoicacid

Intermediate 15S (180 mg, 0.46 mmol) was dissolved in MeOH (20 mL). 2MNaOH (1.16 mL) was added, and the reaction stirred at RT. The reactionmixture was concentrated under reduced pressure, neutralized with 2NHCl, the precipitated solid material filtered off to give 160 mg (92%yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.27-1.44 (m, 2 H) 1.62-1.74 (m, 2 H)1.83-1.94 (m, 1 H) 1.95-2.07 (m, 2 H) 2.08-2.20 (m, 2 H) 2.38-2.45 (m, 2H) 3.31-3.38 (m, 2 H) 3.81 (s, 1 H) 3.88 (dd, J=11.37, 2.78 Hz, 2 H)3.96 (d, J=6.57 Hz, 2 H) 7.48 (dd, J=2.40, 1.39 Hz, 1 H) 7.61 (dd,J=2.40, 1.64 Hz, 1 H) 7.68 (d, J=0.76 Hz, 1 H) 7.98 (t, J=1.52 Hz, 1 H)13.17-13.32 (m, 1 H).

Intermediate 17A (3S)-Tetrahydrofuran-3-ylmethyl4-methylbenzenesulfonate

A solution of (3R)-tetrahydrofuran-3-ylmethanol (3.0 g, 29.4 mmol), TEA(6.1 mL, 44 mmol) and trimethylamine hydrochloride (281 mg, 2.9 mmol)were stirred in DCM (90 mL) at RT for 10 minutes and cooled to 0° C.4-Methylbenzenesulfonyl chloride (6.16 g, 32 mmol) was added and themixture stirred at RT for 17 h. The mixture was treated withN,N-dimethylethane-1,2-diamine (3.8 mL, 35 mmol) and water. The aqueouslayer was extracted three times with DCM. The combined organic portionswere concentrated under reduced pressure and purified via columnchromatography (silica gel, hexane/EE gradient) to give 6.45 g (86%yield) of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.45 (td, J=13.09, 6.97 Hz, 1 H)1.79-1.96 (m, 1 H) 1.83-1.83 (m, 1 H) 2.43 (s, 3 H) 3.27-3.36 (m, 1 H)3.48-3.68 (m, 3 H) 3.88-4.01 (m, 2 H) 7.49 (d, J=7.91 Hz, 2 H) 7.75-7.84(m, 2 H).

Intermediate 18 Methyl3-bromo-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

Intermediate 1 (4.85 g, 21 mmol), Intermediate 17A (6.45 g, 25.2 mmol)and caesium carbonate (10.2 g, 31.5 mmol) were stirred in DMF (81 mL) at50° C. for 60 h. The reaction mixture was cooled to RT, filtered and thefiltrate concentrated under reduced pressure to give the crude titlecompound (7.47 g) which was used in the next step without furtherpurification.

Intermediate 14T Methyl3-[(3S)-tetrahydrofuran-3-ylmethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Intermediate 18 (7.47 g, 23.7 mmol), bis(pinacolato)diborane (15.05 g,59.3 mmol), potassium acetate (8.14 g, 83 mmol) and Pd(dppf)Cl₂ (1.73 g,2.37 mmol) in 1,4-dioxane (91 mL) were stirred at 90° C. for 80 hours.The reaction mixture was cooled to RT and concentrated in vacuo. Theremaining crude reaction mixture was extracted with DCM, washed withwater and the organic phase concentrated in vacuo. The crude materialwas purified by column chromatography (silica gel, hexane/EE gradient)to give the title compound 9.3 g (quantitative yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.31 (s, 12 H) 1.63-1.75 (m, 1 H)1.95-2.07 (m, 1 H) 2.58-2.69 (m, 1 H) 3.54 (dd, J=8.59, 5.56 Hz, 1 H)3.66 (d, J=6.82 Hz, 1 H) 3.72-3.83 (m, 2 H) 3.86 (s, 3 H) 3.99 (dd,J=19.07, 7.20 Hz, 2 H) 7.39 (dd, J=2.78, 0.76 Hz, 1 H) 7.55 (dd, J=2.65,1.64 Hz, 1 H) 7.83-7.87 (m, 1 H).

Intermediate 15T Methyl3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

Intermediate 14T (1 g, 2.76 mmol), 2-chloro-5-cyclobutyl-1,3-thiazole(623 mg, 3.59 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (338 mg, 0.41 mmol) weredissolved in 1M K₂CO₃ aqueous solution (6.63 mL) and THF (45 mL). Thereaction mixture was heated under reflux for 2 hours. The reactionmixture was concentrated under reduced pressure. The crude material waspurified by column chromatography (silica gel, hexane/EE gradient) toafford the title compound 770 mg (75% yield).

Intermediate 5T3-(5-Cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoicacid

Intermediate 15T (770 mg, 2.06 mmol) was dissolved in MeOH (20 mL) andTHF (20 mL). 2M NaOH (4.12 mL) was added, and the reaction stirred atRT. The reaction mixture was concentrated under reduced pressure. Waterwas added and the aqueous phase adjusted to pH 2 with 2N HCl, extractedwith EE and the organics concentrated under reduced pressure to give 765mg (quantitative yield) of the title compound which was used withoutfurther purification.

Intermediate 15U Methyl3-(5-ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

Intermediate 14R (1.05 g, 2.79 mmol), 2-chloro-5-ethyl-1,3-thiazole (495mg, 3.34 mmol) and Pd(dppf)Cl₂ (306 mg, 0.42 mmol) were dissolved in 1MK₂CO₃ aqueous solution (6.6 mL) and THF (42 mL). The reaction mixturewas heated at 120° C. for 90 minutes in the microwave. The reactionmixture was concentrated under reduced pressure, the remaining materialdiluted with water and extracted three times with DCM. The combinedorganics were concentrated under reduced pressure. Crude material waspurified by column chromatography (silica gel, hexane/EE gradient) toafford the title compound 450 mg (44% yield).

Intermediate 5U3-(5-Ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoicacid

Intermediate 15U (450 mg, 1.25 mmol) was dissolved in MeOH (50 mL). 2MNaOH (3.1 mL) was added, and the reaction stirred at RT. The reactionmixture was concentrated under reduced pressure, neutralized with 2NHCl, the mixture extracted three times with EE and the combined organicsconcentrated under reduced pressure. The remaining material was purifiedby column chromatography (silica gel, hexane/EE gradient) to give 50 mg(12% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.29 (t, J=7.45 Hz, 3 H) 1.31-1.43 (m,2 H) 1.65-1.75 (m, 2 H) 1.97-2.08 (m, 1 H) 2.90 (d, J=7.58 Hz, 2 H)3.31-3.38 (m, 2 H) 3.84-3.92 (m, 2 H) 3.95 (d, J=6.32 Hz, 2 H) 7.50 (s,1 H) 7.55 (s, 1 H) 7.66 (s, 1 H) 7.98 (s, 1 H).

Intermediate 15V Methyl3-(5-isopropyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

Intermediate 14R (716 mg, 1.90 mmol),2-chloro-5-(propan-2-yl)-1,3-thiazole (370 mg, 2.28 mmol) andPd(dppf)Cl₂.CH₂Cl₂ (233 mg, 0.29 mmol) were dissolved in 1M K₂CO₃aqueous solution (4.6 mL) and THF (28 mL). The reaction mixture washeated at 120° C. for 90 minutes in the microwave. The reaction mixturewas concentrated under reduced pressure, the remaining material dilutedwith water and extracted three times with DCM. The combined organicswere concentrated under reduced pressure. Crude material was purified bycolumn chromatography (silica gel, hexane/EE gradient) to afford thetitle compound 330 mg (46% yield).

Intermediate 5V3-(5-Isopropyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoicacid

Intermediate 15V (330 mg, 0.88 mmol) was dissolved in MeOH (50 mL). 2MNaOH (2.2 mL) was added, and the reaction stirred at RT. The reactionmixture was concentrated under reduced pressure, neutralized with 2NHCl, the mixture extracted three times with EE and the combined organicsconcentrated under reduced pressure. The remaining material was purifiedby column chromatography (silica gel, hexane/EE gradient) to give 140 mg(32% yield) of the title compound which was used without furtherpurification.

Intermediate 17B Tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate

A solution of tetrahydro-2H-pyran-4-ol (25.0 g, 245 mmol), TEA (51 mL,367 mmol) and trimethylamine hydrochloride (2.34 g, 24.5 mmol) werestirred in DCM (750 mL) at RT for 10 minutes and cooled to 0° C.4-Methylbenzenesulfonyl chloride (51.3 g, 269 mmol) was added and themixture stirred at RT for 17 h. The mixture was treated withN,N-dimethylethane-1,2-diamine (31.6 mL, 294 mmol) and water.

The aqueous layer was extracted three times with DCM. The combinedorganic portions were concentrated under reduced pressure and purifiedvia column chromatography (silica gel, hexane/EE gradient) to give 58.5g (93% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.51-1.61 (m, 2 H) 1.74 (dq, J=13.04,3.65 Hz, 2 H) 2.42 (s, 3 H) 3.39 (ddd, J=11.75, 8.97, 3.03 Hz, 2 H) 3.71(dt, J=11.81, 4.71 Hz, 2 H) 4.69 (tt, J=8.65, 4.23 Hz, 1 H) 7.47 (d,J=8.08 Hz, 2 H) 7.81 (d, J=8.34 Hz, 2 H).

Intermediate 14W Methyl3-(tetrahydro-2H-pyran-4-yloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Intermediate 24 (0.85 g, 2.7 mmol), bis(pinacolato)diborane (1.71 g,6.74 mmol), potassium acetate (0.93 g, 9.44 mmol) and Pd(dppf)Cl₂ (0.20g, 0.27 mmol) in 1,4-dioxane (50 mL) was stirred at 80° C. untilcomplete conversion. The reaction mixture was cooled to RT andconcentrated in vacuo. The remaining crude reaction mixture wasextracted with DCM, and the organic phase concentrated in vacuo. Thecrude material was purified by column chromatography (silica gel,hexane/EE gradient) to give the title compound 1.06 g (quantitativeyield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.27-1.33 (m, 12 H) 1.60 (s, 2 H)1.89-1.98 (m, 2 H) 3.51 (s, 2 H) 3.78-3.87 (m, 5 H) 4.66-4.74 (m, 1 H)7.42 (dd, J=2.76, 0.75 Hz, 1 H) 7.58 (dd, J=2.51, 1.51 Hz, 1 H)7.83-7.86 (m, 1 H).

Intermediate 15W Methyl3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoate

Intermediate 14W (500 mg, 1.38 mmol), 2-chloro-5-cyclobutyl-1,3-thiazole(288 mg, 1.66 mmol), Pd(dppf)Cl₂ (151 mg, 0.21 mmol) were dissolved in1M K₂CO₃ aqueous solution (3.3 mL) and THF (25 mL). The reaction mixturewas heated at 90° C. until complete conversion. The reaction mixture wasconcentrated under reduced pressure, the remaining material diluted withwater and extracted three times with DCM. The combined organics wereconcentrated under reduced pressure. Crude material was purified bycolumn chromatography (silica gel, hexane/EE gradient) to afford thetitle compound 320 mg (62% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.55-1.69 (m, 2 H) 1.91 (br. s., 1 H)1.95-2.04 (m, 3 H) 2.12-2.21 (m, 2 H) 2.43 (d t, J=8.27, 3.19 Hz, 2 H)3.53 (ddd, J=11.68, 9.03, 3.03 Hz, 2 H) 3.81-3.91 (m, 6 H) 4.79 (s, 1 H)7.53 (dd, J=2.40, 1.39 Hz, 1 H) 7.64-7.72 (m, 2 H) 8.00 (t, J=1.52 Hz, 1H).

Intermediate 5W3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoicacid

Intermediate 15W (320 mg, 0.86 mmol) was dissolved in MeOH. 2M NaOH (2.1mL) was added, and the reaction stirred at RT. The reaction mixture wasconcentrated under reduced pressure, adjusted to pH 2 with 2N HCl,extracted with EE and concentrated under reduced pressure to give 114 mg(37% yield) of the title compound, which was used without furtherpurification.

Intermediate 15X Methyl3-(5-ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoate

Intermediate 14W (500 mg, 1.38 mmol), 2-chloro-5-ethyl-1,3-thiazole (245mg, 1.66 mmol) and Pd(dppf)Cl₂ (151 mg, 0.21 mmol) were dissolved in 1MK₂CO₃ aqueous solution (3.3 mL) and THF (25 mL). The reaction mixturewas heated at 90° C. until complete conversion. The reaction mixture wasconcentrated under reduced pressure, the remaining material diluted withwater and extracted three times with DCM. The combined organics wereconcentrated under reduced pressure. Crude material was purified bycolumn chromatography (silica gel, hexane/EE gradient) to afford thetitle compound 320 mg (62% yield).

Intermediate 5X3-(5-Ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid

Intermediate 15X (450 mg, 1.29 mmol) was dissolved in MeOH. 2M NaOH(2.59 mL) was added, and the reaction stirred at RT. The reactionmixture was concentrated under reduced pressure, adjusted to pH 2 with2N HCl, extracted with EE and concentrated under reduced pressure togive 251 mg (58% yield) of the title compound, which was used withoutfurther purification.

Intermediate 15Y Methyl 3-bromo-5-(2-methoxyethoxy)benzoate

A mixture of Intermediate 1 (300 g, 1.3 mol), 2-bromoethyl methyl ether(330 g, 2.37 mol), K₂CO₃ (330 g, 2.39 mol) and NaI (2 g) in acetonitrile(2500 mL) was refluxed for 12 h. The suspension was filtered, solid waswashed with acetonitrile (1000 mL) and combined filtrate was evaporatedunder reduced pressure to give a dark oil. Petroleum ether (2500 mL) wasadded and the formed solution was filtered through a layer of aluminumoxide. The filtrate was evaporated under reduced pressure to give 250.3g of the title compound (67% yield).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 3.30 (s, 3 H) 3.61-3.69 (m, 2 H) 3.86(s, 3 H) 4.14-4.24 (m, 2 H) 7.43 (dd, J=2.45, 1.32 Hz, 1 H) 7.48 (t,J=2.17 Hz, 1 H) 7.63 (t, J=1.51 Hz, 1 H).

Intermediate 5Y 3-Bromo-5-(2-methoxyethoxy)benzoic acid

Intermediate 15Y (5.0 g, 17.3 mmol) was dissolved in MeOH (52 mL). 2MNaOH (17.3 mL) was added, and the reaction stirred at RT. The reactionmixture was adjusted to pH 3 with 1N HCl, extracted with EE, dried(Na₂SO₄) and concentrated under reduced pressure to give 5.12 g (>100%)of the title compound, which was used without further purification.

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 3.30 (s, 3 H) 3.65 (dd, J=5.27, 3.58Hz, 2 H) 4.18 (dd, J=5.27, 3.58 Hz, 2 H) 7.39-7.45 (m, 2 H) 7.61 (t,J=1.51 Hz, 1 H) 13.26-13.53 (m, 1 H).

Intermediate 19Z Tert-butyl4-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate

Intermediate 3 (500 mg, 2.0 mmol), tert-butyl4-hydroxypiperidine-1-carboxylate (807 mg, 4.0 mmol) andtriphenylphosphine (2104 mg, 8.0 mmol) were combined in THF and cooledto 0° C. in an ice bath. DIAD (0.788 mL, 4.0 mmol) was added dropwiseand the reaction mixture stirred for 10 min before warming to RT. Afterstirring for 16 h the reaction mixture was concentrated in vacuo, takenup in EtOAc (10 mL), washed with brine (5 mL) and ammonium chloridesolution (5 mL). The organic phase was separated, dried (over MgSO₄) andconcentrated in vacuo to give a brown oil. Purification by BiotageIsolera™ chromatography (on a pre-packed 50 g SiO₂, eluting with EtOAcin heptane 0-100%) gave 1000 mg (92% yield) of the title compound as acolourless oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm]=8.08 (t, J=1.4 Hz, 1H), 7.69(dd, J=2.4, 1.6 Hz, 1H), 7.58 (dd, J=2.5, 1.4 Hz, 1H), 7.51 (d, J=1.2Hz, 1H), 4.62 (tt, J=6.9, 3.5 Hz, 1H), 3.93 (s, 3H), 3.77-3.62 (m, 2H),3.47-3.31 (m, 2H), 2.52 (d, J=1.1 Hz, 3H), 2.03-1.88 (m, 3H), 1.87-1.55(m, 5H), 1.48 (s, 9H).

LCMS (Analytical Method A) Rt=1.65 min, MS (ESIpos): m/z=433 (M+H)⁺.

Intermediate 5Z3-{[1-(Tert-butoxycarbonyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a solution of tert-butyl4-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate(1000 mg, 1.85 mmol) in THF (2.5 mL) was added 1M LiOH (2.7 mL) and theresulting solution stirred for 16 h at RT. The organic solvent wasremoved in vacuo and the aqueous phase acidified to pH ˜4 with 1M HCl.The resulting precipitate was collected by filtration and evaporated togive 682 mg (88% yield) of the title compound as a white solid.

LCMS (Analytical Method A) R_(t)=1.48 min, MS (ESIpos): m/z=419 (M+H)⁺.

Intermediate 19AA Methyl3-[(3R)-1-methylpyrrolidin-3-yl]oxy-5-(5-methyl-1,3-thiazol-2-yl)benzoate

To a solution of Intermediate 3 (150 mg, 0.60 mmol),(3S)-1-methylpyrrolidin-3-ol (121 mg, 1.20 mmol) and triphenylphosphine(631 mg, 2.41 mmol) in THF (3 mL) at 0° C. was added DIAD (236 μL, 1.20mmol) dropwise. The solution was stirred for a further 5 mins at 0° C.then allowed to warm to RT and stirred for a further 16 h. The reactionmixture was concentrated in vacuo, taken up in DCM and washed withbrine, saturated NaHCO₃, dried (over MgSO₄) and concentrated in vacuo togive a brown oil. The crude material was purified by Biotage Isolera™chromatography (on a pre-packed KP-NH column, eluting withheptane-acetone 5:1 to 1:4) to give 143 mg (54% yield) of the titlecompound as a clear oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm]=8.10 (t, J=1.5 Hz, 1H), 7.62(dd, J=2.5, 1.6 Hz, 1H), 7.56-7.48 (m, 2H), 4.99-4.89 (m, 1H), 3.93 (s,3H), 2.95-2.76 (m, 3H), 2.52 (d, J=1.1 Hz, 3H), 2.40 (s, 5H), 2.12-1.95(m, 1H), 1.69-1.57 (m, 1H)

LCMS (Analytical Method A) R_(t)=0.93 min, MS (ESIpos) m/z=534 (M+H)⁺.

Intermediate 19AB Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-pyrrolidin-3-yloxy]benzoate

To a 0° C. stirred solution of Intermediate 3 (150 mg, 0.60 mmol),tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (225 mg, 1.20 mmol)and triphenylphosphine (63 mg, 2.40 mmol) in THF (3 mL) was added DIAD(236 μL, 1.20 mmol) dropwise. The solution was stirred at 0° C. for 5min then allowed to warm to RT and stirred for a further 16 h. Thereaction mixture was concentrated in vacuo, taken up in DCM and washedwith brine, saturated NaHCO₃, dried (over Mg₂SO₄) and concentrated invacuo to give a brown oil. Purification by Biotage Isolera™chromatography (pre-packed 10 g cartridge, eluting with heptane-EtOAc,15:3 to 0:1) to give a colourless oil (620 mg). The oil was dissolved inDCM (1 mL) and TFA (1 mL) and the solution stirred for 1 h at RT. Thereaction mixture was concentrated in vacuo, taken up in DCM (1 mL) andstirred for 15 mins in saturated sodium bicarbonate. The organic phasewas collected and dried (over MgSO₄) and concentrated in vacuo to give400 mg (34% yield) of the title compound as an amber oil.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.10 (t, J=1.3 Hz, 1H),7.73-7.65 (m, 1H), 7.65-7.57 (m, 2H), 3.94 (s, 3H), 2.54 (d, J=1.0 Hz,3H), 1.26 (s, 12H), 1.25 (s, 9H).

LCMS (Analytical Method A) R_(t)=0.96, MS (ESIpos) m/z=319 (M+H)⁺.

Intermediate 20 Methyl3-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-pyrrolidin-3-yloxy]benzoate(420 mg, 0.40 mmol), formaldehyde (37% solution in water, 59 μL, 0.79mmol) and formic acid (59 μL, 1.58 mmol) were combined in THF and heatedat reflux for 4 h. The reaction mixture was concentrated in vacuo, takenup in sodium bicarbonate and extracted with DCM. The organic phase wasdried (over MgSO₄) and concentrated in vacuo to give 65 mg (49% yield)of the title compound.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.12 (t, J=1.4 Hz, 1H), 7.64(dd, J=2.4, 1.6 Hz, 1H), 7.55 (dd, J=2.5, 1.4 Hz, 6H), 7.53 (d, J=1.2Hz, 1H), 5.06-4.93 (m, 6H), 3.95 (s, 3H), 2.92-2.82 (m, 3H), 2.54 (d,J=1.1 Hz, 3H), 2.51-2.36 (m, 5H), 2.10-2.00 (m, 2H).

Intermediate 21 Tert-butyl3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]azetidine-1-carboxylate

Intermediate 3 (300 mg, 1.20 mmol), tert-butyl3-{[(4-methylphenyl)sulfonyl]oxy}azetidine-1-carboxylate (511 mg, 1.80mmol) and cesium carbonate (780 mg, 2.39 mmol) were combined in drydimethylformamide (3 mL) under an atmosphere of nitrogen and heated to80° C. for 16 h. The room temperature reaction mixture was poured ontobrine (3 mL) and extracted with ethyl acetate (10 mL). The organic phasewas washed with brine (3 mL), dried (over MgSO₄) and concentrated invacuo to give a brown oil. The crude material was purified by BiotageIsolera™ chromatography (silica gel, eluting with heptane-tertbutylmethyl ether, 3:1 to 0:1) to give 440 mg (81% yield) of the titlecompound as a colourless oil that crystallised on standing.

¹H NMR (250 MHz, CDCl3): δ [ppm]=1.45 (s, 9H), 2.52 (d, 3H), 3.94 (s,3H), 4.02 (dd, 2H), 4.36 (dd, 2H), 5.00 (tt, 1H), 7.41 (dd, 1H),7.48-7.58 (m, 2H), 8.12 (t, 1H).

Intermediate 22 Methyl3-(azetidin-3-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Tert-butyl3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]azetidine-1-carboxylate(440 mg, 0.98 mmol) was stirred in 4 M HCl in dioxane (2.5 mL) for 2 h.The reaction was concentrated to dryness and the resulting soliddissolved in saturated NaHCO₃ and extracted with DCM/Methanol (9:1, 2×25mL). The organic phase was dried (over MgSO₄) and concentrated todryness to give 259 mg (87% yield) of the title compound.

LCMS (Analytical Method A) R_(t)=0.92 min, MS (ESIpos) m/z=305 (M+H)⁺.

Intermediate 23 Methyl3-[(1-methylazetidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

To a solution of methyl3-(azetidin-3-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (255 mg, 0.84mmol) in DCE (0.5 mL) was added formaldehyde (37% aqueous solution, 1mL) and acetic acid (0.048 mL) and the resulting mixture stirred at RTfor 30 min. Sodium triacetoxyborohydride (213 mg, 1.00 mmol) was addedand the mixture stirred at RT for a further 16 h. The reaction mixturewas concentrated in vacuo and the residue basified to pH 9 withsaturated sodium bicarbonate solution and extracted into ethyl acetate.The organic phase was separated, dried (over MgSO₄) and concentrated invacuo to give a brown oil. The crude material was purified by BiotageIsolera™ chromatography to give 80 mg (29% yield) of the title compoundas a colourless oil.

¹H NMR (500 MHz, MeOD): δ [ppm]=2.53 (d, 3H), 3.27-3.31 (m, 2H),3.83-3.90 (m, 2H), 3.93 (s, 3H), 4.92 (p, 1H), 7.44 (dd, 1H), 7.50-7.57(m, 2H), 8.04 (t, 1H).

Intermediate 24 Methyl 3-bromo-5-(tetrahydro-2H-pyran-4-yloxy)benzoate

Intermediate 1 (1.5 g, 6.49 mmol), Intermediate 17B (2.5 g, 9.74 mmol)and caesium carbonate (3.17 g, 9.74 mmol) were stirred in DMF (25 mL) atRT until complete conversion. The reaction mixture was filtered and thefiltrate concentrated under reduced pressure. The remaining material waspurified via column chromatography (silica gel, hexane/EE gradient) togive the title compound, 0.85 g (42% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.59 (s, 2 H) 1.92-1.99 (m, 2 H) 3.49(s, 2 H) 3.80-3.86 (m, 5 H) 4.65-4.81 (m, 1 H) 7.45 (dd, J=2.41, 1.39Hz, 1 H) 7.52-7.54 (m, 1 H) 7.62 (t, J=1.52 Hz, 1 H).

Intermediate 4AC Methyl3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A solution of Intermediate 3 (250 mg, 1.0 mmol),2-bromo-5-methyl-1,3,4-thiadiazole (270 mg, 1.5 mmol) and cesiumcarbonate (654 mg, 2.0 mmol) in DMF (5 mL) was heated in the microwaveat 120° C. for 1 h. The reaction mixture partitioned between brine (10mL) and EtOAc (10 mL). The layers were separated and the aqueous layerwas extracted with further EtOAc (2×10 mL). The combined organics werewashed with brine (20 mL), dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude material was purified by BiotageIsolera™ chromatography (silica gel, eluting with heptane-EtOAc, 4:1 to1:4) to afford 226.6 mg (65% yield) of the title compound as a yellowgum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.39 (t, J=1.4 Hz, 1H), 8.09(dd, J=2.3, 1.7 Hz, 1H), 7.98 (dd, J=2.4, 1.4 Hz, 1H), 7.54 (d, J=1.1Hz, 1H), 3.95 (s, 3H), 2.69 (s, 3H), 2.54 (d, J=1.0 Hz, 3H).

LCMS (Analytical Method A) Rt=1.23 min, MS (ESIpos): m/z=347.9 (M+H)⁺.

Intermediate 5AC3-[(5-Methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 4AC (226 mg, 0.65 mmol) was stirred in MeOH (2.5 mL), THF(2.5 mL) and 1M LiOH (2.5 mL) for 1 h. The reaction mixture wasconcentrated under reduced pressure and the residue taken up in water (5mL) and washed with EtOAc (5 mL). The aqueous layer was acidified with1M HCl to pH ˜3 and the precipitate formed was collected by vacuumfiltration to afford 198.6 mg (92% yield) of the title compound as anoff-white powder.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 8.30 (t, J=1.5 Hz, 1H), 8.13-8.10 (m,1H), 7.94-7.89 (m, 1H), 7.70 (d, J=1.2 Hz, 1H), 2.65 (s, 3H).

LCMS (Analytical Method A) Rt=1.08 min, MS (ESIpos): m/z=333.9 (M+H)⁺.

Intermediate 4AD Tert-butyl3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]azetidine-1-carboxylate

Intermediate 3 (300 mg, 1.20 mmol), tert-butyl3-{[(4-methylphenyl)sulfonyl]oxy}azetidine-1-carboxylate (443 mg, 1.56mmol) and caesium carbonate (784 mg, 2.04 mmol) were combined in MeCN (5mL) and heated to 100° C. for 2 h. On cooling to RT the reaction mixturewas diluted with EtOAc (5 mL) and filtered before being concentratedunder reduced pressure. The crude material was purified by BiotageIsolera™ chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to3:2) to afford 303.7 mg (57% yield) of the title compound as anoff-white solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.13 (t, J=1.3 Hz, 1H),7.57-7.55 (m, 1H), 7.53 (d, J=1.1 Hz, 1H), 7.42 (dd, J=2.4, 1.3 Hz, 1H),5.05-4.97 (m, 1H), 4.37 (dd, J=10.0, 6.6 Hz, 2H), 4.03 (dd, J=9.8, 3.9Hz, 2H), 3.94 (s, 3H), 2.53 (d, J=0.9 Hz, 3H), 1.45 (s, 9H).

LCMS (Analytical Method A) Rt=1.37 min, MS (ESIpos): m/z=405.05 (M+H)⁺.

Intermediate 5AD3-{[1-(Tert-butoxycarbonyl)azetidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 4AD (303 mg, 0.68 mmol) was dissolved in MeOH (5 mL) andTHF (5 mL). 1M LiOH (2 mL) was added, and the reaction stirred at RT for2 h. The reaction mixture was concentrated to remove MeOH/THF, and theresidue taken up in water (5 mL) and washed with EtOAc (5 mL). Theaqueous layer was acidified to pH 4 with 1M HCl and the solutionextracted with DCM (3×5 mL) to afford 205.6 mg (77% yield) of the titlecompound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.28 (s, 1H), 7.60-7.58 (m, 1H),7.58-7.57 (m, 1H), 7.46 (dd, J=2.4, 1.3 Hz, 1H), 5.02 (ddd, J=10.4, 6.3,4.1 Hz, 1H), 4.39 (dd, J=9.9, 6.5 Hz, 2H), 4.05 (dd, J=9.8, 4.0 Hz, 2H),2.58-2.49 (m, 3H), 1.46 (s, 9H).

LCMS (Analytical Method A) Rt=1.19 min, MS (ESIpos): m/z=391.00 (M+H)⁺.

Intermediate 4AE Tert-butyl(3S)-3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]pyrrolidine-1-carboxylate

To a solution of Intermediate 3 (250 mg, 1.0 mmol), tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate (375 mg, 2 mmol) andtriphenylphosphine (1.05 g, 4 mmol) in THF (5 mL) cooled to 0° C. wasadded DIAD (394 μL, 2 mmol) dropwise. The solution was stirred at 0° C.for 5 min then allowed to warm to RT and stirred for a further 72 h. Thereaction mixture was then concentrated under reduced pressure and thecrude material was purified by Biotage Isolera™ chromatography (silicagel, eluting with heptane-EtOAc, 20:1 to 2:3) to give 745 mg (88% yield,50% purity) of the title compound as a colourless gum.

¹H NMR (500 MHz, Chloroform-d) δ [ppm] 8.11 (d, J=7.2 Hz, 1H), 7.68 (s,1H), 7.56 (s, 1H), 7.53 (s, 1H), 5.04 (s, 1H), 3.94 (s, 3H), 3.68 (s,3H), 3.30 (s, 1H), 2.53 (s, 3H), 2.26-2.09 (m, 2H), 1.27 (s, 9H).

LCMS (Analytical Method A) Rt=1.37 min, MS (ESIpos): m/z=419.1 (M+H)⁺.

Intermediate 5AE3-[(3S)-1-Tert-butoxycarbonylpyrrolidin-3-yl]oxy-5-(5-methylthiazol-2-yl)benzoicacid

To a solution of Intermediate 4AE (745 mg, 50% purity, 0.89 mmol)dissolved in THF (2 mL) and MeOH (5 mL) was added 1 M LiOH (2.5 mL) andthe resulting solution stirred at RT for 2 h. The reaction mixture wasconcentrated to remove MeOH/THF, and the residue taken up in water (5mL) and washed with EtOAc (5 mL). The aqueous layer was acidified to pH4 with 1M HCl then extracted with DCM (3×10 mL). The combined organicswere dried over MgSO₄, filtered and concentrated under reduced pressureto afford 296.3 mg (82% yield) of the title compound as white powder.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 7.99 (t, J=1.4 Hz, 1H), 7.65 (d,J=1.2 Hz, 1H), 7.62-7.59 (m, 1H), 7.48 (dd, J=2.5, 1.3 Hz, 1H), 5.19 (s,1H), 3.51 (dd, J=39.9, 10.7 Hz, 4H), 2.08 (s, 2H), 1.40 (s, 9H).

LCMS (Analytical Method A) Rt=1.21 min, MS (ESIpos): m/z=405.10 (M+H)⁺.

Intermediate 4AF tert-butyl3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate

Intermediate 3 (1.3 g, 3.65 mmol, 70% purity), tert-butyl4-hydroxypiperidine-1-carboxylate (1.47 g, 7.3 mmol) andtriphenylphosphine (3.8 g, 14.6 mmol) were combined in THF (10 mL) andcooled to 0° C. in an ice bath. DIAD (1.43 mL, 7.3 mmol) was addeddropwise and the reaction mixture stirred for 10 min then allowed towarm to RT and stirred for a further 16 h. The reaction mixture wasconcentrated under reduced pressure, taken up in DCM (20 mL) then washedwith brine (10 mL) and ammonium chloride (10 mL). The organic phase wasseparated, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 0:1) toafford 209 mg (15% yield) of the title compound as colourless oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.10 (t, J=1.4 Hz, 1H),7.72-7.63 (m, 1H), 7.62-7.56 (m, 1H), 7.51 (d, J=1.1 Hz, 1H), 4.52-4.32(m, 1H), 3.93 (s, 3H), 3.81-3.68 (m, 1H), 3.59-3.25 (m, 3H), 2.52 (d,J=1.1 Hz, 3H), 2.14-1.72 (m, 4H), 1.37 (s, 9H).

LCMS (Analytical Method A) Rt=1.60 min, m/z=433 (M+H)⁺.

Intermediate 5AF3-{[1-(tert-butoxycarbonyl)piperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a solution of Intermediate 4AF (367 mg, 0.76 mmol, 90% purity) in THF(2 mL) was added 1 M LiOH (1.1 mL) and the reaction mixture stirred for16 h at RT before concentrating under reduced pressure. The residue wastaken up in water (˜1 mL) and basified to pH 4 with 1 M HCl toprecipitate a white solid that was extracted with EtOAc (2×5 mL). Thecombined organics were dried over MgSO₄, filtered and concentrated underreduced pressure to give a colourless gum that was freeze-dried to give264 mg (77% yield) of the title compound as white powder.

LCMS (Analytical Method A) Rt=1.39, MS (ESIpos) m/z=419 (M+H)⁺.

Intermediate 4AG Methyl3-[(1-acetylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

To a solution of Intermediate 3 (200 mg, 0.80 mmol),1-(4-hydroxypiperidin-1-yl)ethanone (126 mg, 0.88 mmol) andtriphenylphosphine (630 mg, 2.40 mmol) in THF (2 mL) cooled to 0° C. wasadded DIAD (0.3 mL, 1.53 mmol) dropwise. The resulting solution wasallowed to warm to RT and stirred for 16 h. LCMS analysis showedcomplete conversion to desired product thus the mixture was concentratedunder reduced pressure. The residue was dissolved in DCM (10 mL) andwashed with NH₄Cl (5 mL). The organic phase was separated, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by Biotage Isolera™ chromatography (silica gel,eluting with heptane-EtOAc, 1:4 to 0:1 followed by EtOAc-MeOH, 1:0 to20:3) to give 182 mg (52% yield) of the title compound as yellow gum.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.08 (t, 1H), 7.70 (dd, 1H),7.58 (dd, 1H), 7.51 (d, 1H), 4.69 (tt, 1H), 3.93 (s, 3H), 3.77-3.61 (m,3H), 3.52-3.34 (m, 1H), 2.52 (d, 3H), 2.12 (s, 3H), 2.01-1.79 (m, 4H).

LCMS (Analytical Method A) Rt=1.28 min, MS (ESIpos): m/z=375.1 (M+H)⁺.

Intermediate 5AG3-[(1-acetylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a solution of Intermediate 4AG (182 mg, 0.44 mmol, 90% purity) in THF(1 mL) was added 1 M LiOH solution (0.65 mL) and the resulting mixturewas stirred at RT for 2 h before being concentrated under reducedpressure. The residue was taken up in water (4 mL), acidified to pH 4with 1 M HCl solution then extracted with 1:1 IPA/chloroform (2×20 mL).The combined organics were dried over MgSO₄, filtered and concentratedunder reduced pressure to give 120 mg (76% yield) of the title compoundas white solid.

¹H NMR (500 MHz, DMSO): δ [ppm] 7.96 (t, 1H), 7.65-7.63 (m, 2H), 7.53(dd, 1H), 4.85-4.75 (m, 1H), 3.87-3.77 (m, 1H), 3.72-3.63 (m, 1H), 2.02(s, 3H), 2.01-1.86 (m, 2H), 1.72-1.61 (m, 1H), 1.61-1.49 (m, 1H).

LCMS (Analytical Method A) Rt=1.13 min, MS (ESIpos) m/z=361 (M+H)⁺.

Intermediate 4AH Tert-butyl6-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-2-azaspiro[3.3]heptane-2-carboxylate

A solution of Intermediate 3 (250 mg, 0.702 mmol, 70% purity),tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (225 mg, 1.06mmol) and triphenylphosphine (735 mg, 2.80 mmol) in THF (3 mL) under anatmosphere of nitrogen was cooled to 0° C. in an ice bath and DIAD (0.2mL, 1.07 mmol) was added dropwise. The resulting solution was allowed towarm to RT and stirred for 16 h. LCMS (Analytical Method A) showedapprox. 50% conversion to product. A further portion of DIAD (0.1 mL,0.54 mmol) was added and the mixture stirred for a further 24 h. LCMS(Analytical Method A) still showed incomplete conversion therefore afurther portion of tert-butyl6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (40 mg, 0.19 mmol) andDIAD (0.1 mL, 0.54 mmol) was added and stirred for a further 16 h. Themixture was then concentrated under reduced pressure, and the residuetriturated with heptane to precipitate triphenylphosphine oxide whichwas removed by filtration. The residue was concentrated under reducedpressure and the residue purified by Biotage Isolera™ chromatography(silica gel, eluting with heptane-EtOAc, 4:1 to 2:3) to give 250 mg (76%yield) of the title compound as a colourless gum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.08 (t, J=1.4 Hz, 1H),7.57-7.49 (m, 2H), 7.44 (dd, J=2.4, 1.4 Hz, 1H), 4.69 (p, J=6.6 Hz, 1H),4.00 (s, 2H), 3.93 (d, J=3.7 Hz, 5H), 2.81-2.73 (m, 2H), 2.52 (d, J=1.0Hz, 3H), 2.40-2.32 (m, 2H), 1.44 (s, 9H).

LCMS (Analytical Method A) Rt=1.64 min, MS (ESIpos) 445 (M+H)⁺.

Intermediate 5AH3-{[2-(tert-butoxycarbonyl)-2-azaspiro[3.3]hept-6-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a solution of Intermediate 4AH (250 mg, 0.534 mmol, 95% purity) inTHF (1 mL) was added 1 M LiOH solution (0.8 mL) and the resultingsolution stirred for 16 h before concentrating under reduced pressure.The residue was taken up in water (1 mL) and acidified to pH 5 with 1 MHCl to precipitate a white solid which was collected by filtration toafford 160 mg (66% yield) of the title compound as white powder.

¹H NMR (250 MHz, DMSO): δ [ppm] 7.96 (t, 1H), 7.64 (d, 1H), 7.54-7.44(m, 1H), 7.37 (dd, 1H), 4.78 (q, 1H), 3.93 (s, 2H), 3.83 (s, 2H),2.81-2.65 (m, 2H), 2.35-2.19 (m, 2H), 1.37 (s, 9H).

LCMS (MS17, 2 min) Rt=1.42 min, MS (ESIpos) m/z=431 (M+H)⁺.

Intermediate 47 Methyl3-({trans-3-[(tert-butoxycarbonyl)amino]cyclobutyl}oxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 3 (500 mg, 2.00 mmol), cis-tert-butyl3-hydroxycyclobutylcarbamate (488.2 mg, 2.6 mmol) and triphenylphosphine(2104 mg, 8.0 mmol) were combined in THF (10 mL) and cooled to 0° C.DIAD (0.79 mL, 4.0 mmol) was added dropwise and the reaction mixturestirred for 10 min then allowed to warm to RT and stirred for a further96 h. The reaction mixture was concentrated under reduced pressure, andpurified by Biotage Isolera™ chromatography (silica gel, eluting withheptane-EtOAc, 9:1 to 3:7) to afford 1.6 mg (74% yield) of the titlecompound as a colourless oil.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.09 (t, J=1.4 Hz, 1H), 7.54(dd, J=2.4, 1.6 Hz, 1H), 7.51 (d, J=1.0 Hz, 1H), 7.44 (dd, J=2.5, 1.4Hz, 1H), 4.94-4.87 (m, 1H), 4.31 (s, 1H), 3.93 (s, 3H), 2.63-2.53 (m,2H), 2.52 (d, J=1.2 Hz, 3H), 2.48-2.39 (m, 2H), 1.45 (s, 9H).

LCMS (Analytical Method A) Rt=1.53 min, MS (ESIpos): m/z=419.05 (M+H)⁺.

Intermediate 48 Methyl3-[(trans-3-aminocyclobutyl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 47 (1.6 g, 39% purity, 1.5 mmol) was stirred inhydrochloric acid (4M in 1,4-dioxane, 1.5 ml, 6.0 mmol) and DCM (10 mL)for 2 h. The reaction mixture was concentrated under reduced pressureand the residue taken up in water (15 mL) and washed with EtOAc (2×15mL). The aqueous layer was basified to pH 8 with sat. NaHCO₃ solutionand the mixture extracted with DCM (3×15 mL). The combined organics weredried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was loaded in methanol onto a pre-washed SCX-2 cartridge, whichwas washed with further methanol, followed by 2M NH₃ in MeOH to elutethe product. The material was further purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 1:3 to 0:1)afford 477 mg (80% yield) of the title compound.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.09 (t, J=1.5 Hz, 1H), 7.55(dd, J=2.4, 1.6 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.46 (dd, J=2.5, 1.4Hz, 1H), 4.98-4.94 (m, 1H), 3.93 (s, 3H), 3.82 (tt, J=7.7, 5.2 Hz, 1H),2.52 (d, J=1.1 Hz, 3H), 2.48 (ddt, J=10.8, 7.2, 3.4 Hz, 2H), 2.30-2.19(m, 2H).

LCMS (Analytical Method A) Rt=0.95 min, MS (ESIpos): m/z=319.0 (M+H)⁺.

Intermediate 49 Methyl3-{[trans-3-(dimethylamino)cyclobutyl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 48 (477 mg, 80% purity, 1.19 mmol) was dissolved inmethanol (10 mL) and acetic acid (0.5 mL). Formaldehyde (133 μl, 4.79mmol) followed by STAB (762 mg, 3.60 mmol) was added, and the reactionstirred for 2 h. LCMS (Analytical Method A) showed incompleteconversion, hence the reaction was re-treated with formaldehyde (133 μl,4.79 mmol) followed by STAB (762 mg, 3.60 mmol) and stirred for afurther 4 h. LCMS (Analytical Method A) still showed incompleteconversion, hence the reaction was again re-treated with formaldehyde(266 μl, 9.58 mmol) followed by STAB (1.53 g, 7.2 mmol) and stirred overthe weekend. The reaction mixture was concentrated under reducedpressure, and the residue taken up in sat. NaHCO₃ (30 mL), and thesolution extracted with DCM (3×30 mL). The combined organics were driedover MgSO₄, filtered and concentrated under reduced pressure to afford477.7 mg (92% yield) of the title compound as a colourless gum.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.09 (t, J=1.5 Hz, 1H), 7.55(dd, J=2.5, 1.6 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.46 (dd, J=2.5, 1.4Hz, 1H), 4.87 (tt, J=6.7, 3.5 Hz, 1H), 3.93 (s, 3H), 3.01-2.89 (m, 1H),2.52 (d, J=1.1 Hz, 3H), 2.48-2.30 (m, 4H), 2.18 (s, 7H).

LCMS (Analytical Method A) Rt=1.00 min, MS (ESIpos): m/z=347.1 (M+H)⁺.

Intermediate 5AI3-{[Trans-3-(dimethylamino)cyclobutyl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 49 (477 mg, 80% purity, 1.1 mmol) was dissolved in MeOH (5mL) and THF (5 mL). 1M LiOH (2 mL) was added, and the reaction stirredat RT for 2 h. The reaction mixture was concentrated to remove MeOH/THF,and the residue taken up in water (5 mL) and washed with EtOAc (5 mL).The aqueous layer was acidified to pH 6 with 1M HCl and the solutionextracted with 1:1 IPA/chloroform (3×5 mL). The combined organics weredried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was freeze-dried from acetonitrile/water to afford 230 mg (57%yield) of the title compound as a white solid.

¹H NMR (500 MHz, DMSO): δ [ppm] 8.00 (s, 1H), 7.62 (d, J=1.1 Hz, 1H),7.40 (s, 2H), 4.85 (s, 1H), 2.88 (p, J=7.5 Hz, 1H), 2.43-2.33 (m, 2H),2.24-2.16 (m, 2H), 2.10 (s, 6H). thiazole methyl group obscured bysolvent.

LCMS (Analytical Method A) Rt=0.92 min, MS (ESIpos): m/z=333.0 (M+H)⁺.

Intermediate 6AJTert-butyl-3-fluoro-4-{[(4-methylphenyl)sulfonyl]oxy}piperidine-1-carboxylate,as a mixture of 2 trans isomers

Tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (750 mg, 3.42mmol), trimethylamine (0.72 mL, 5.13 mmol) and trimethylaminehydrochloride (33 mg, 0.34 mmol) were stirred in DCM (15 mL).4-Methylbenzenesulfonyl chloride (815 mg, 4.28 mmol) was added. Thereaction was stirred at RT for 4 h. TLC (50% EtOAc in heptane) showedcomplete reaction, hence, the reaction mixture was treated withN,N-dimethylethane-1,2-diamine (225 μL, 2.05 mmol) to consume theunreacted TsCl. The reaction mixture was washed with 1 M HCl (2×5 mL)before being dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 10:1 to 1:1) toafford 606.1 mg (47% yield) of the title compound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.86-7.78 (m, 2H), 7.35 (d,J=8.0 Hz, 2H), 4.71 (d, J=10.0 Hz, 1H), 4.58 (d, J=48.3 Hz, 1H), 3.87(d, J=52.6 Hz, 2H), 3.34 (s, 2H), 2.45 (s, 3H), 2.08 (s, 1H), 1.76-1.67(m, 1H), 1.44 (s, 9H).

Intermediate 4AJTert-butyl-3-fluoro-4-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate,as a mixture of 2 trans isomers

Intermediate 3 (426 mg, 73% purity, 1.25 mmol), Intermediate 6AJ (606mg, 1.62 mmol) and caesium carbonate (610 mg, 1.87 mmol) were combinedin acetonitrile (5 mL) and stirred at 120° C. in the microwave for 3×30min. The reaction mixture was diluted with EtOAc and filtered throughCelite® before being concentrated at reduced pressure. The crudematerial was purified by Biotage Isolera™ chromatography (silica gel,eluting with heptane-EtOAc, 1:0 to 2:3) to afford 387.6 mg (57% yield)of the title compound as a colourless gum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.12 (t, J=1.4 Hz, 1H), 7.74(dd, J=2.4, 1.6 Hz, 1H), 7.62 (dd, J=2.5, 1.3 Hz, 1H), 7.52 (d, J=1.2Hz, 1H), 4.72-4.52 (m, 2H), 3.95 (s, 3H), 3.92-3.77 (m, 1H), 3.66 (s,1H), 3.58 (s, 1H), 3.46 (s, 1H), 2.53 (d, J=1.1 Hz, 3H), 2.20-2.10 (m,1H), 1.84-1.75 (m, 1H), 1.70-1.59 (m, 1H), 1.48 (s, 9H).

LCMS (Analytical Method A) Rt=1.41 min, MS (ESIpos): m/z=451.1 (M+H)⁺.

Intermediate 5AJ3-{[−1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, as a mixture of stereoisomers

Intermediate 4AJ (387 mg, 83% purity, 0.71 mmol) was dissolved in MeOH(5 mL) and THF (5 mL). 1M LiOH (2 mL) was added, and the reactionstirred at RT for 2 h. The reaction mixture was concentrated to removeMeOH/THF, and the residue taken up in water (5 mL) and washed with EtOAc(5 mL). The aqueous layer was acidified to pH 4 with 1M HCl, andextracted with DCM (3×5 mL). The combined organics were dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by Biotage Isolera™ chromatography (silica gel,eluting with heptane-EtOAc, 1:0 to 2:3) to afford 105.2 mg (34% yield)of the title compound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.27-8.21 (m, 1H), 7.80-7.74 (m,1H), 7.70-7.64 (m, 1H), 7.56 (d, J=1.2 Hz, 1H), 4.62 (d, J=22.8 Hz, 2H),3.87 (d, J=58.5 Hz, 1H), 3.61 (s, 2H), 3.45 (s, 1H), 2.54 (d, J=1.0 Hz,3H), 2.20-2.11 (m, 1H), 1.80 (s, 2H), 1.48 (s, 9H).

LCMS (Analytical Method A) Rt=1.16 min, MS (ESIpos): m/z=437.15 (M+H)⁺.

Intermediate 5AK3-[(6-Methylpyridazin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

A solution of Intermediate 3 (130 mg, 0.52 mmol),3-bromo-6-methylpyridazine (135 mg, 0.78 mmol) and caesium carbonate(340 mg, 1.04 mmol) in DMF (2.5 mL) was heated in the microwave to 120°C. for 45 min, then for a further 20 min at the same temperature. Thereaction mixture was concentrated under reduced pressure and the residuetaken up in methanol (5 mL) and treated with 1M LiOH (2.5 mL). After 1.5h, the reaction was concentrated to remove the organics, before beingdiluted with water (10 mL) and extracted with EtOAc (2×10 mL). Theaqueous layer was acidified to ˜pH 4 with 2M HCl, the extracted with DCM(3×10 mL). The combined organics were dried over MgSO₄, filtered andconcentrated under reduced pressure to afford 143 mg (73% yield) of thetitle compound as brown gum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.48 (s, 1H), 8.06 (s, 1H),8.00-7.96 (m, 1H), 7.59 (s, 1H), 7.42 (d, J=9.0 Hz, 1H), 7.19 (d, J=9.0Hz, 1H), 2.70 (d, J=7.7 Hz, 3H), 2.53 (s, 3H).

LCMS (Analytical Method A) Rt=1.01 min, MS (ESIpos): m/z=328.05 (M+H)⁺.

Intermediate 4AY Methyl3-({1-[(tert-butoxycarbonyl)amino]cyclopropyl}methoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 3 (400 mg, 1.6 mmol), tert-butyl[1-(hydroxymethyl)cyclopropyl]carbamate (390.5 mg, 2.01 mmol) andtriphenylphosphine (1683 mg, 6.4 mmol) were combined in THF (10 mL) andcooled to 0° C. in an ice bath. DIAD (0.63 mL, 3.2 mmol) was addeddropwise and the reaction mixture stirred for 10 min before beingallowed to warm to RT and stirred for a further 96 h. The reactionmixture was concentrated under reduced pressure, and purified by BiotageIsolera™ chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to1:1). A second purification by Biotage Isolera™ chromatography (silicagel, eluting with heptane-EtOAc, 20:3) afforded 208.9 mg (23% yield) ofthe title compound as a colourless oil.

LCMS (Analytical Method A) Rt=1.47 min, MS (ESIpos): m/z=419 (M+H)⁺.

Intermediate 5AY3-({1-[(Tert-butoxycarbonyl)amino]cyclopropyl}methoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 4AY (208.9 mg, 0.369 mmol) was stirred in methanol (5 mL)and 1M LiOH (2.5 mL) for 1 h. The organics were removed under reducedpressure, and the residue diluted with water (5 mL) and extracted withEtOAc (5 mL). The aqueous phase was acidified to pH 2 with 2M HCl,before being extracted with DCM (2×5 mL). The combined organics weredried over MgSO₄, filtered and concentrated under reduced pressure toafford 48.1 mg (32% yield) of the title compound as a colourless gum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.20 (s, 1H), 7.70-7.67 (m, 1H),7.64 (s, 1H), 7.57-7.53 (m, 1H), 5.19 (s, 1H), 4.09 (s, 2H), 2.53 (d,J=0.9 Hz, 3H), 1.43 (s, 9H), 0.94 (d, J=19.3 Hz, 4H).

LCMS (Analytical Method A) Rt=1.31 min, MS (ESIpos): m/z=405 (M+H)⁺.

Intermediate 30 3-Hydroxy-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of Intermediate 3 (500 mg, 2.0 mmol) dissolved in THF (5mL) and MeOH (5 mL) was added 2M LiOH (2.5 mL, 5 mmol) and stirred for50° C. for 2 h. The reaction mixture was cooled then concentrated toremove MeOH/THF, and the residue taken up in water (5 mL) and washedwith EtOAc (5 mL). The aqueous layer was acidified to pH 4 with 1M HCland the precipitate collected by vacuum filtration and dried in thevacuum oven to afford 281.1 mg (59% yield) of the title compound as anoff-white powder.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 14.89 (s, 1H), 12.60 (t, J=1.5 Hz,1H), 12.38 (d, J=1.2 Hz, 1H), 12.27-12.22 (m, 1H), 12.14 (dd, J=2.4, 1.4Hz, 1H).

LCMS (Analytical Method A) Rt=0.94 min, MS (ESIpos): m/z=235.95 (M+H)⁺.

Intermediate 323-Hydroxy-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 30 (486 mg, 1.86 mmol), Intermediate VI (465.5 mg, 2.05mmol) and DIPEA (1.30 mL, 7.44 mmol) were combined in DMF (10 mL) andHATU (848.3 mg, 2.23 mmol) was added. The reaction mixture was allowedto stir at room temperature overnight. The crude reaction was quenchedby addition of water (˜15 mL). The resultant emulsion was evaporated toa free-flowing oil. Water (˜15 mL) was added and the resultantprecipitate removed by filtration and washed with a further aliquot ofwater, then allowed to dry in air to give 660 mg (82% yield) of thetitle compound as an off-white powder.

¹H NMR (500 MHz, DMSO-d6): δ [ppm]=10.05 (s, 1H), 9.13-9.09 (m, 3H),7.79 (t, J=1.4, 1H), 7.62 (d, J=1.2, 1H), 7.46-7.39 (m, 1H), 7.37-7.29(m, 1H), 5.28 (m, 1H), 2.49 (s, 3H), 1.59 (d, J=7.1, 3H).

LCMS (Analytical Method F) Rt=2.87 min, MS (ESIpos): m/z=409.1 (M+H)⁺.

Intermediate 633-Hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,mixture of 2 trans isomers

To a solution of3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid (145mg, 0.47 mmol), Intermediate VI (129 mg, 0.57 mmol) and DIPEA (0.25 mL,1.42 mmol) in DCM (2 mL) was added HATU (269 mg, 0.71 mmol). The mixturewas stirred for 2 h at RT then diluted with DCM and washed with waterand saturated aqueous ammonium chloride solution. The organic phase wasseparated, dried (MgSO₄), filtered and concentrated at reduced pressure.The crude material was purified by Biotage Isolera™ chromatography(eluting with 0-7% MeOH in DCM on a pre-packed KP-SiO₂ column) to give222 mg (88% yield) of the title compound.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.79 (s, 1H),7.55-7.43 (m, 2H), 7.35 (s, 1H), 6.92 (d, J=6.6 Hz, 1H), 5.36 (m, 1H),4.45 (dt, J=6.4, 3.4 Hz, 1H), 4.04 (s, 1H), 2.79 (s, 6H), 2.53 (s, 3H),1.71 (d, J=7.1 Hz, 4H), 1.32-1.23 (m, 6H)

LCMS (Analytical Method D) Rt=4.22 min, MS (ESIpos) m/z=481 (M+H)⁺.

Intermediate 763-(5-Chloro-1,3-thiazol-2-yl)-5-{[trans-3-hydroxybutan-2-yl]oxy}benzoicacid, as a Mixture of Trans Isomers

To a solution of methyl 3-hydroxy-5-(5-chloro-1,3-thiazol-2-yl)benzoate(500 mg, 1.67 mmol) and trans-2,3-epoxybutane (0.63 mL, 6.67 mmol) inDMSO (5 mL) was added caesium carbonate (2.17 g, 6.67 mmol). The mixturewas heated to 100° C. for 16 h then diluted with water (10 mL) andwashed with EtOAc (10 mL). The aqueous layer was acidified with conc.HCl and extracted into DCM (2×15 mL). The combined organics were driedover MgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by Biotage Isolera™ chromatography (silica gel,eluting with DCM/MeOH, 1:0 to 4:1) followed by preparative HPLC (MethodB) to afford 306 mg (56% yield) of the title compound as an off-whitesolid.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 8.00 (s, 1H), 7.94 (t, J=1.4 Hz, 1H),7.64-7.60 (m, 1H), 7.55 (dd, J=2.4, 1.4 Hz, 1H), 4.82 (s, 1H), 4.47-4.32(m, 1H), 3.85-3.69 (m, 1H), 1.24 (d, J=6.2 Hz, 3H), 1.14 (d, J=6.4 Hz,3H).

LCMS (Analytical Method D) Rt=3.84 min, MS (ESIpos): m/z=327.97 (M+H)⁺.

The mixture of trans isomers was separated using Chiral Purification(Method 1) to give Intermediate 77 (Trans Isomer 1) and Intermediate 78(Trans Isomer 2)

Intermediate 77 Trans Isomer 1;3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}benzoic acid

SFC Chiral Purification (Method 1) on 296 mg of Intermediate 76 gave98.4 mg of the title compound as an off-white solid.

SFC Chiral Analysis (Method 1): 96.2% e.e. Rt=2.71 min.

¹H NMR (250 MHz, DMSO-d6) δ[ppm]=7.99 (s, 1H), 7.94 (s, 1H), 7.61 (s,1H), 7.55 (s, 1H), 4.82 (s, 1H), 4.52-4.28 (m, 1H), 3.75 (s, 1H), 1.23(d, J=6.2 Hz, 3H), 1.13 (d, J=6.4 Hz, 3H).

Intermediate 78 Trans Isomer 2;3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}benzoic acid

SFC Chiral Purification (Method 1) on 296 mg of Intermediate 76 gave93.2 mg of the title compound as an off-white solid.

SFC Chiral Analysis (Method 1): 97.2% e.e. Rt=3.18 min.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 8.00 (s, 1H), 7.97-7.88 (m, 1H),7.64-7.59 (m, 1H), 7.56-7.51 (m, 1H), 4.83 (d, J=5.1 Hz, 1H), 4.49-4.33(m, 1H), 3.85-3.70 (m, 1H), 1.23 (d, J=6.2 Hz, 3H), 1.13 (d, J=6.4 Hz,3H).

Intermediate 873-Hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid, as aMixture of Trans Isomers

To a solution of Intermediate 3 (300 mg, 0.88 mmol) andtrans-2,3-epoxybutane (0.32 mL, 3.51 mmol) in DMSO (3 mL) was addedcaesium carbonate (1145 mg, 3.51 mmol). The mixture heated to 100° C.for 16 h then diluted with water (10 mL) and acidified with conc. HCl toform a white precipiate which was extracted into IPA/CHCl3 (1:3) (2×25mL). The combined organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC (Method B) to give 500 mg (57% yield) of the titlecompound as an off-white solid.

The mixture of trans isomers was separated using Chiral Purification(Method 1) to give Intermediate 88 (Trans Isomer 1) and Intermediate 89(Trans Isomer 2)

Intermediate 88 Trans Isomer 1;3-Hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

SFC Chiral Purification (Method 1) on 298.2 mg of Intermediate 87 gave183.6 mg of the title compound as an off-white powder.

SFC Chiral Analysis (Method 1): 100% e.e. Rt=2.17 min.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 7.96-7.92 (m, 1H), 7.66-7.59 (m, 2H),7.51-7.47 (m, 1H), 4.43-4.32 (m, 2H), 3.82-3.71 (m, 1H), 1.24 (d, J=6.2Hz, 3H), 1.14 (d, J=6.4 Hz, 3H).

Intermediate 89 Trans Isomer 2;3-Hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

SFC Chiral Purification (Method 1) on 298.2 mg of Intermediate 89 gave46.7 mg of the title compound as an off-white powder.

SFC Chiral Analysis (Method 1): 100% e.e. Rt=2.41 min.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 13.25 (s, 1H), 7.97-7.91 (m, 1H),7.67-7.58 (m, 2H), 7.53-7.47 (m, 1H), 4.81 (d, J=5.1 Hz, 1H), 4.43-4.31(m, 1H), 3.82-3.70 (m, 1H), 1.24 (d, J=6.1 Hz, 3H), 1.14 (d, J=6.4 Hz,3H.

Intermediate 923-Hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid, as aMixture of Cis Isomers

To a solution of Intermediate 3 (780 mg, 3.13 mmol) andcis-2,3-epoxybutane (1.09 mL, 12.5 mmol) in DMSO (10 mL) was addedcaesium carbonate (4.08 g, 12.5 mmol). The mixture heated to 100° C. for16 h then diluted with water (30 mL) and acidified to pH 4 with 2N HClto form a white precipiate which was extracted into IPA/CHCl3 (1:1) (30mL). The combined organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by BiotageIsolera™ chromatography (eluting with 0-80% EtOAc in heptane on a 50 gpre-packed KP-SiO₂ column) to give 565 mg (55% yield) of the titlecompound as an off-white powder.

Intermediate 253-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

3-Bromo-5-fluoro benzonitrile (30 g, 150 mmol), bis(pinacolato)diborane(41.9 g, 0.15 mol) and potassium acetate (44.2 g, 0.45 mol) werecombined in 1,4-dioxane (300 mL) and degassed with N₂ for 10 mins.[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (5.5 g,7.5 mmol) was added and the mixture degassed with N₂ for a further 10min before heating at 100° C. under an atmosphere of nitrogen for 18 h.The mixture was filtered through Celite® and the solids washed withethyl acetate. The filtrate was washed with brine, the organic phaseseparated, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified by filtration through a silicaplug, eluting with EtOAc, and the resultant filtrate concentrated underreduced pressure to afford 43.7 g (quantitative yield assumed, 84%purity) of the title compound as brown oil

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 1.31 (s, 12H), 7.65-7.72 (m, 1H),7.79-7.83 (m, 1H), 8.00 (ddd, J=8.8, 2.7, 1.4 Hz, 1H).

LCMS (Analytical Method A) Rt=0.91 min.

Intermediate 26 3-Fluoro-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

Intermediate 25 (15 g, 51 mmol), 2-bromo-5-methyl-1,3-thiazole (5.9 mL,56 mmol) and potassium carbonate (17.6 g, 127.5 mmol) were dissolved in4:1 1,4-dioxane/water (200 mL). The solution was with N₂ for 10 min.Tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol) was added andthe reaction mixture heated at 80° C. for 16 h. After this time thereaction mixture was partitioned between water and EtOAc. The organicphase was separated and the aqueous phase extracted with further EtOAc.The combined organics were washed with brine, dried (MgSO₄), filteredand concentrated under reduced pressure. The crude material was purifiedby Biotage Isolera™ chromatography (silica gel, eluting withheptanes-EtOAc, 1:0 to 4:1). The product containing fractions werecombined and triturated with heptane and the precipitate collected anddried by vacuum filtration. The mother liqueur and mixed fractions werecombined and concentrated. The residue was re-purified by BiotageIsolera™ chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to4:1). The two batches were combined to afford 7.06 g (59% yield) of thetitle compound as white powder.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.96 (t, J=1.4 Hz, 1H), 7.86(ddd, J=9.2, 2.4, 1.6 Hz, 1H), 7.57 (d, J=1.1 Hz, 1H), 7.35 (ddd, J=7.7,2.5, 1.3 Hz, 1H), 2.55 (d, J=1.1 Hz, 3H).

LCMS (Analytical Method A) Rt=1.26 min, MS (ESIpos): m/z=218.85 (M+H)⁺.

Intermediate 29 3-(5-Ethyl-1,3-thiazol-2-yl)-5-fluorobenzonitrile

Intermediate 26 (5 g, 17 mmol), 2-chloro-5-ethyl-1,3-thiazole (3 g, 20mmol) and cesium carbonate (14 g, 42.5 mmol) were dissolved in 4:11,4-dioxane/water (50 mL). The solution was degassed with a stream ofnitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (982 mg,0.85 mmol) was added and the reaction mixture stirred at 100° C.overnight. The reaction was diluted with water (20 mL) and extractedwith DCM (2×50 mL). The combined organics were washed with brine (30mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 3:1). Theproduct containing fractions were concentrated and the residuecrystallised from heptane to afford 2.5 g (63% yield) of the titlecompound as white crystalline solid.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.97 (d, J=1.3 Hz, 1H),7.91-7.79 (m, 1H), 7.59 (s, 1H), 7.35 (ddd, J=7.7, 2.4, 1.3 Hz, 1H),3.01-2.82 (m, 2H), 1.37 (t, J=7.5 Hz, 3H).

LCMS (Analytical Method A) Rt=1.34 min, MS (ESIpos): m/z=232.9 (M+H)⁺.

Intermediate 54 Tert-butyl(3-endo)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate

To a solution of (3-endo)-8-azabicyclo[3.2.1]octan-3-ol (3 g, 23.6 mmol)and triethylamine (5.1 mL, 36.6 mmol) in DCM (30 mL) was addeddi-tert-butyl dicarbonate (10.3 g, 47.2 mmol) portionwise and theresulting reaction mixture stirred at RT for 16 h. The reaction mixturewas diluted with water then the organic layer was separated and washedwith saturated citric acid (aq), water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure thentriturated with heptane to afford 4.16 g (77% yield) of the titlecompound as an off-white crystalline solid.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 1.38 (s, 9H), 1.61 (d, J=13.5 Hz,2H), 1.70-1.96 (m, 4H), 2.12 (d, J=6.7 Hz, 2H), 3.94 (d, J=19.0 Hz, 3H),4.56 (d, J=2.3 Hz, 1H).

Intermediate 27AL Tert-butyl(3-endo)-3-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-8-azabicyclo[3.2.1]octane-8-carboxylate

To a stirred solution of Intermediate 54 (1.56 g, 8.86 mmol) in dry DMF(10 mL) was added NaH (60% dispersion in mineral oil, 274 mg, 6.85mmol). After the mixture was stirred for 15 min Intermediate 26 (1.0 g,4.58 mmol) was added in one portion. The resulting mixture was stirredfor 18 h. After this time the reaction mixture was quenched with brineand extracted with EtOAc. The organic phase was separated and washedwith brine, dried over MgSO₄, filtered and evaporated under reducedpressure. The crude material was purified Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 1:1) toafford 1.25 g (58% yield) of the title compound.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.67 (t, J=1.4 Hz, 1H),7.67-7.57 (m, 1H), 7.53 (d, J=1.2 Hz, 1H), 7.08 (dd, J=2.4, 1.3 Hz, 1H),4.72 (t, J=4.7 Hz, 1H), 4.22 (s, 2H), 2.54 (d, J=1.1 Hz, 3H), 2.33-1.89(m, 9H), 1.47 (d, J=4.7 Hz, 9H)

LCMS (Analytical Method A) Rt=1.49 min, MS (ESIpos) m/z=426 (M+H)⁺.

Intermediate 28AL3-{[(3-endo)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a solution of Intermediate 27AL (1.25 g, 2.64 mmol) in DMSO (5 mL)was added 2 M NaOH (2 mL) and the mixture stirred at 110° C. for 3 h.The mixture was slowly acidified with 2M HCl to pH˜5 to precipitate awhite solid which was collected by filtration. The solids were dried ina vacuum oven, which resulted in melting of the compound, affording 290mg (53% yield) of the title compound as a colourless gum.

LCMS (Analytical Method A) Rt=1.32 min, MS (ESIpos) m/z=445 (M+H)⁺.

Intermediate 63 Tert-butyl(3-exo)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate

To a solution of (3-exo)-8-azabicyclo[3.2.1]octan-3-ol (0.95 g, 7.5mmol) and triethylamine (1.7 mL, 12.2 mmol) in DCM (10 mL) was addeddi-tert-butyl dicarbonate (3.27 g, 15.0 mmol) portionwise and theresulting reaction mixture stirred at RT for 16 h. The reaction mixturewas diluted with water then the organic layer was separated and washedwith saturated citric acid (aq), water and brine. The organic layer wasdried over MgSO₄, filtered and concentrated under reduced pressure toafford 1.65 g (97% yield) of the title compound as an off white solid.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 4.41-3.95 (m, 3H), 2.00-1.53 (m,9H), 1.45 (s, 9H).

Intermediate 27AM Tert-butyl(3-exo)-3-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-8-azabicyclo[3.2.1]octane-8-carboxylate

To a stirred solution of Intermediate 63 (0.68 g, 2.98 mmol) in dry DMF(10 mL) was added NaH (60% dispersion in mineral oil, 120 mg, 3.00mmol). After the mixture was stirred for 15 min Intermediate 26 (0.5 g,2.29 mmol) was added as one portion. The resulting mixture was stirredat RT for 48 h. The reaction mixture was poured onto brine and extractedinto EtOAc. The organic layer was washed with brine, separated, driedover MgSO₄, filtered and concentrated under reduced pressure to givebrown oil. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 0:1) toafford 531 mg (54% yield) of the title compound as an off-white powder.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.71 (t, J=1.4 Hz, 2H),7.68-7.63 (m, 1H), 7.53 (d, J=1.2 Hz, 1H), 7.13 (dd, J=2.4, 1.3 Hz, 1H),4.75 (tt, J=10.6, 5.9 Hz, 1H), 4.34 (s, 2H), 2.53 (d, J=1.1 Hz, 3H),2.20-2.00 (m, 4H), 1.93-1.65 (m, 4H), 1.49 (s, 9H).

LCMS (Analytical Method A) Rt=1.46 min, MS (ESIpos): m/z=426.05 (M+H)⁺.

Intermediate 28AM3-{[(3-exo)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a solution of Intermediate 27AL (1.25 g, 2.64 mmol) in DMSO (5 mL)was added 2 M aqueous sodium hydroxide (2 mL) and the mixture stirred at110° C. for 3 h. The mixture was slowly acidified by 2 M aqueous HCl topH˜5 to precipitate a white solid which was collected by filtration. Thesolids were dried in a vacuum oven to give 0.56 g (48% yield) of thetitle compound as an off-white powder.

LCMS (Analytical Method A) Rt=1.35 min, MS (ESIpos) m/z=445 (M+H)⁺.

Intermediate 27AN3-[(3-methyloxetan-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a solution of 3-methyloxetan-3-ol (121 mg, 1.37 mmol) in dry DMF (2mL) was added NaH (60% dispersion in mineral oil, 55 mg, 1.38 mmol) andthe mixture stirred at RT for 1 h before addition of Intermediate 26(200 mg, 0.92). The resulting mixture was stirred at RT for 3 h thenpartitioned between EtOAc and water. The organic phase was separated andthe aqueous phase extracted with EtOAc. The combined organics werewashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure. TLC analysis (EtOAc-heptane, 1:1) indicated incompleteconsumption of SM. The residue was dissolved in DMF (1 mL) and added toa pre-stirred solution of 3-methyloxetan-3-ol (121 mg, 1.37 mmol) andNaH (60% dispersion in mineral oil, 55 mg, 1.38 mmol). The mixture wasstirred at RT overnight at which point TLC analysis indicatedconsumption of starting material. The mixture was partitioned betweenEtOAc and water. The organic phase was separated and the aqueous phaseextracted with EtOAc. The combined organics were washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude material was purified by Biotage Isolera™ chromatography (silicagel, eluting with heptane-EtOAc, 1:0 to 2:3) to give 140 mg (51% yield)of the title compound as brown oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.73 (t, J=1.4 Hz, 1H), 7.53 (d,J=1.2 Hz, 1H), 7.40 (dd, J=2.4, 1.5 Hz, 1H), 6.86 (dd, J=2.4, 1.3 Hz,1H), 4.94 (d, J=6.6 Hz, 2H), 4.64 (d, J=7.3 Hz, 2H), 2.54 (d, J=1.1 Hz,3H), 1.79 (s, 3H)

LCMS (Analytical Method A) Rt=1.18 min, MS (ESIpos) m/z=287 (M+H)⁺.

Intermediate 28AN3-[(3-methyloxetan-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 27AN (140 mg, 0.46 mmol) was stirred in 2M NaOH (2.3 mL)and DMF (1 mL) at 110° C. for 14 h in a sealed tube. THF was added toaid dissolution and the resulting solution was heated for 16 h at 110°C. in a sealed tube. A further portion of 2 M NaOH solution (2 mL) wasadded and heated to 110° C. for 3 h. The mixture was acidified with 2MHCl to form a white precipitate that was extracted into EtOAc. Theorganic phase was separated, dried over MgSO₄, filtered and concentratedunder reduced pressure to give 118 mg (75% yield) of the title compoundas white powder.

LCMS (Analytical Method A) Rt=1.05 min, MS (ESIpos) m/z=306 (M+H)⁺.

Intermediate 27AO Tert-butyl(3S)-3-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate

To a solution of tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (415mg, 2.06 mmol) in dry DMF (3 mL) was added NaH (60% dispersion inmineral oil, 88 mg, 2.2 mmol) and the mixture stirred at RT for 1 hbefore addition of Intermediate 26 (300 mg, 1.38 mmol). The resultingmixture was stirred at RT for 16 h then partitioned between EtOAc andwater. The organic phase was separated and the aqueous phase extractedwith EtOAc. The combined organics were washed with brine, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by Biotage Isolera™ chromatography (silica gel,eluting with heptane-EtOAc, 4:1 to 1:4) to afford 510 mg (93% yield) ofthe title compound.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.72-7.68 (m, 1H), 7.68-7.63 (m,1H), 7.53-7.49 (m, 1H), 7.16-7.12 (m, 1H), 4.36 (tt, J=6.8, 3.3 Hz, 1H),3.96-3.11 (m, 4H), 2.51 (s, 3H), 2.07-1.96 (m, 1H), 1.91-1.72 (m, 2H),1.60-1.50 (m, 1H), 1.48-1.26 (m, 9H).

Intermediate 573-{[(3S)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a solution of Intermediate 27AO (510 mg, 1.28 mmol) in DCM (5 mL) wasadded TFA (0.5 mL, 6.49 mmol) and the mixture stirred at RT overnight.The mixture was diluted with DCM and poured onto saturated sodiumbicarbonate solution. The organic phase was separated, and the aqueousphase extracted with DCM. The combined organics were dried over MgSO₄,filtered and concentrated under reduced pressure. The resulting solidswere dissolved in DCE (3 mL) then formaldehyde, 37% solution in water (1mL, 1.08 mmol) and acetic acid (0.1 mL, 1.04 mmol) were added. Thesolution was stirred at RT for 15 min before the addition of STAB (540mg, 2.55 mmol) portionwise, which was subsequently stirred for 2 h. Thereaction mixture was diluted with DCM and poured onto saturated sodiumbicarbonate solution. The organic phase was separated and the aqueousextracted with further DCM. The combined organics were dried over MgSO₄,filtered and concentrated under reduced pressure. The crude material waspurified by Biotage Isolera™ chromatography (silica gel, eluting withheptane-TBME, 2:3 to 0:1) to give 172 mg (43% yield) of the titlecompound.

LCMS (Analytical Method A) Rt=0.85 min, MS (ESIpos) m/z=314 (M+H)⁺.

Intermediate 28AO :3-{[(3S)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 57 (172 mg, 0.55 mmol) and 2M NaOH (5.5 mL, 11.0 mmol) wereheated together at 110° C. in a sealed tube for 6 h. On cooling to RTthe mixture was acidified to pH 11 and extracted with IPA/CHCl3 (1:4)(3×15 mL). The combined organics were dried over MgSO₄ and concentratedunder reduced pressure to give 130 mg (71% yield) of the title compoundas white powder LCMS (Analytical Method A) Rt=0.80 min, MS (ESIpos)m/z=333 (M+H)⁺.

Intermediate 27AP Tert-butyl(3R)-3-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate

To a solution of tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (415mg, 2.06 mmol) in dry DMF (3 mL) was added NaH (60% dispersion inmineral oil, 88 mg, 2.2 mmol) and the mixture stirred at RT for 1 hbefore addition of Intermediate 26 (300 mg, 1.38 mmol). The resultingmixture was stirred at RT for 16 h then partitioned between EtOAc andwater. The organic phase was separated and the aqueous phase extractedwith EtOAc. The combined organics were washed with brine, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by Biotage Isolera™ chromatography (silica gel,eluting with heptane-EtOAc, 4:1 to 1:4) to give 452 mg (82% yield) ofthe title compound.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.72 (t, J=1.3 Hz, 1H),7.70-7.65 (m, 1H), 7.55-7.50 (m, 1H), 7.18-7.13 (m, 1H), 4.38 (tt,J=6.9, 3.4 Hz, 1H), 4.02-3.09 (m, 4H), 2.53 (d, J=0.9 Hz, 3H), 2.11-1.97(m, 1H), 1.95-1.71 (m, 2H), 1.61-1.30 (m, 10H).

LCMS (Analytical Method A) Rt=1.38 min, MS (ESIpos) m/z=400 (M+H)⁺.

Intermediate 583-{[(3R)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

Intermediate 27AP (452 mg, 1.28 mmol) in DCM (5 mL) was added TFA (0.4mL, 5.19 mmol) and the mixture stirred at RT overnight. The mixture wasdiluted with DCM and poured onto saturated aqueous sodium bicarbonatesolution. The organic phase was separated, and the aqueous phaseextracted with DCM. The combined organics were dried over MgSO₄,filtered and concentrated under reduced pressure.

The resulting solids were dissolved in DCE (3 mL) then formaldehyde, 37%solution in water (0.4 mL, 5.33 mmol) and acetic acid (0.1 mL, 1.04mmol) was added. The solution was stirred at RT for 15 min before theaddition of STAB (480 mg, 2.27 mmol) portionwise, which was subsequentlystirred for 2 h. The reaction mixture was diluted with DCM and pouredonto saturated aqueous sodium bicarbonate solution. The organic phasewas separated and the aqueous extracted with further DCM. The combinedorganics were dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-TBME, 2:3 to 0:1) togive 183 mg (52% yield) of the title compound.

LCMS (Analytical Method A) Rt=0.84 min, MS (ESIpos) m/z=314 (M+H)⁺.

Intermediate 28AP3-{[(3R)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 58 (183 mg, 0.58 mmol) and 2 M NaOH (5.8 mL, 11.6 mmol)were heated together at 110° C. in a sealed tube for 6 h. On cooling toRT the mixture was acidified to pH 11 and extracted with IPA/CHCl₃ (1:4)(3×15 mL). The combined organics were dried over MgSO₄, filtered andconcentrated under reduced pressure to give 185 mg (95% yield) of thetitle compound as white powder.

LCMS (Analytical Method A) Rt=0.81 min, MS (ESIpos) m/z=333 (M+H)⁺.

Intermediate 27AR3-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of (3R)-1-azabicyclo[2.2.2]octan-3-olhydrochloride (0.29 g, 1.79 mmol) in dry DMF (5 mL) was added NaH (60%dispersion in mineral oil, 137 mg, 3.44 mmol). After the mixture wasstirred for 15 min Intermediate 26 (0.3 g, 1.38 mmol) was added as oneportion. The resulting mixture was stirred at RT for 18 h. The reactionmixture was poured onto brine and extracted with EtOAc. The organiclayer was washed with brine, separated, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified byBiotage Isolera™ chromatography (silica gel, eluting with heptane-EtOAc,3:2 to 0:1 followed by EtOAc-MeOH, 1:0 to 4:1) to afford 258.8 mg (51%yield) of the title compound as a yellow gum, which crystallised onstanding.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.70 (t, J=1.4 Hz, 1H), 7.64(dd, J=2.4, 1.6 Hz, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.11 (dd, J=2.4, 1.3Hz, 1H), 4.55-4.44 (m, 1H), 3.42-3.31 (m, 1H), 3.07-2.96 (m, 1H),2.96-2.79 (m, 4H), 2.54 (d, J=1.1 Hz, 3H), 2.23-2.17 (m, 1H), 2.03-1.95(m, 1H), 1.80 (ddt, J=14.0, 9.3, 4.3 Hz, 1H), 1.67-1.58 (m, 1H),1.50-1.40 (m, 1H).

LCMS (Analytical Method A) Rt=0.94 min, MS (ESIpos): m/z=326 (M+H)⁺.

Intermediate 28AR3-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid-formic acid

Intermediate 27AR (258 mg, 0.7 mmol) was stirred in 2 M NaOH (3.5 mL)and DMSO (3.5 mL) at 110° C. for 3 h. After cooling to RT the mixturewas slowly acidified to pH ˜2, before being concentrated under reducedpressure to afford the crude material in DMSO. The crude material waspurified by preparative HPLC (Method A). The product containingfractions were concentrated and the residue freeze-dried from MeCN/waterto afford 146.4 mg (53% yield) of the title compound as an off-whitepowder.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 8.21 (s, 1H), 7.96 (s, 1H), 7.64 (d,J=1.2 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.48 (s, 1H), 4.71 (s, 1H), 3.44(d, J=13.1 Hz, 1H), 3.04-2.77 (m, 4H), 2.21 (d, J=11.9 Hz, 1H), 1.94 (s,1H), 1.74 (s, 2H), 1.51 (s, 1H)

LCMS (Analytical Method A) Rt=0.91 min, MS (ESIpos): m/z=345 (M+H)⁺.

Intermediate 27AS3-(1-Azabicyclo[2.2.2]oct-4-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of quinuclidin-4-ol (250 mg, 1.97 mmol) in dry DMF(4 mL) was added NaH (60% dispersion in mineral oil, 78 mg, 1.95 mmol).After the mixture was stirred for 15 min Intermediate 26 (286 mg, 1.31mmol) was added as one portion and the resulting mixture was stirred atRT for 24 h. A further portion of NaH (78 mg, 1.95 mmol) was added alongwith DBU (1 mL) and finally Intermediate 26 (286 mg, 1.31 mmol). Theresulting mixture was stirred at RT for 16 h. The reaction mixture wasquenched with saturated sodium bicarbonate solution and extracted intoEtOAc. The organic phase was separated, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified bypreparative HPLC (Method A). The product containing fractions wereconcentrated and the residue freeze-dried from MeCN/water to afford 111mg (26% yield) of the title compound as beige powder.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.86 (t, J=1.4 Hz, 1H), 7.72 (t,J=1.9 Hz, 1H), 7.58-7.49 (m, 1H), 7.25-7.21 (m, 1H), 3.11-2.97 (m, 6H),2.53 (d, 3H), 1.90-1.76 (m, 6H).

LCMS (Analytical Method A) Rt=1.00 min, MS (ESIpos) m/z=326 (M+H)⁺.

Intermediate 28AS3-(1-Azabicyclo[2.2.2]oct-4-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 27AS (111 mg, 0.34 mmol) was suspended in 2 M NaOH (2.5 mL)and heated to 120° C. in a sealed tube for 1 h to give a yellowsolution. The mixture was acidified to pH 6 and concentrated underreduced pressure to give 531 mg (>100% yield) of the title compound aspale yellow solid. The crude material was used in the next step withoutpurification.

LCMS (Analytical Method A) Rt=0.90 min, MS (ESIpos) m/z=345 (M+H)⁺.

Intermediate 65Tert-butyl-4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate, as amixture of 2 cis isomers

Sodium borohydride (71 mg, 1.87 mmol) was added at −10° C. to a solutionof 1-boc-2-trifluoromethyl-piperidin-4-one (250 mg, 0.94 mmol) in MeOH(8 mL) and the reaction stirred at −10° C. for 1 h. Sat. aq. NH₄Cl (3mL) was added, and the resulting mixture allowed to warm to RT. The MeOHwas removed under reduced pressure, and the resulting aqueous layerextracted with DCM (4×5 mL). The combined organics were washed withbrine, dried over MgSO₄, filtered and concentrated under reducedpressure to afford 247.6 mg (98% yield) of the title compound ascolourless oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 4.84-4.62 (m, 1H), 4.15-3.95 (m,2H), 3.39-3.18 (m, 1H), 2.10-2.00 (m, 1H), 1.91-1.57 (m, 3H), 1.47 (s,9H).

Intermediate 27ATTert-butyl-4-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-2-(trifluoromethyl)piperidine-1-carboxylate,as a mixture of 2 cis isomers

To a stirred solution of Intermediate 65 (125 mg, 0.467 mmol) in dry DMF(2 mL) was added NaH (60% dispersion in mineral oil, 19 mg, 0.49 mmol)to give a white precipitate. After the mixture was stirred for 15 minIntermediate 26 (85 mg, 0.39 mmol) was added as one portion. Theresulting mixture was stirred for at RT for 18 h. The reaction mixturewas poured onto brine and extracted into EtOAc. The organic layer waswashed with brine, separated, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified byBiotage

Isolera™ chromatography (silica gel, eluting with heptane-EtOAc, 100:1to 3:2) to afford 111.1 mg (61% yield) of the title compound as browngum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.71 (t, J=1.3 Hz, 1H),7.68-7.65 (m, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.14 (dd, J=2.3, 1.3 Hz, 1H),4.78 (s, 1H), 4.76-4.72 (m, 1H), 4.15-4.06 (m, 1H), 3.36 (s, 1H), 2.54(d, J=1.1 Hz, 3H), 2.36 (d, J=15.6 Hz, 1H), 2.13-1.97 (m, 3H), 1.90-1.81(m, 1H), 1.49 (s, 9H).

LCMS (Analytical Method A) Rt=1.48 min, MS (ESIpos): m/z=468 (M+H)⁺.

Intermediate 28AT3-{[1-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, as a mixture of 2 cis isomers

Intermediate 27AT (111 mg, 0.22 mmol) was stirred in 2 M NaOH (1.5 mL)and DMSO (1.5 mL) at 130° C. for 3 h. After cooling to RT the organicswere removed under reduced pressure, then the residue diluted with water(3 mL) and slowly acidified to pH ˜4 with 1M HCl then extracted withEtOAc (3×10 mL). The combined organics were dried over MgSO₄, filteredand concentrated under reduced pressure to afford 104.8 mg (83% yield)of the title compound as colourless gum.

¹H NMR (500 MHz, Chloroform-d) δ 8.19 (t, J=1.3 Hz, 1H), 7.73-7.68 (m,1H), 7.62-7.59 (m, 1H), 7.56 (s, 1H), 4.85-4.70 (m, 2H), 4.07 (d, J=19.4Hz, 1H), 3.38 (s, 1H), 2.53 (d, J=1.0 Hz, 3H), 2.38 (d, J=15.5 Hz, 1H),2.14-2.07 (m, 2H), 2.06-1.97 (m, 2H), 1.89-1.80 (m, 1H), 1.49 (s, 9H).

LCMS (Analytical Method A) Rt=1.34 min, MS (ESIpos): m/z=487 (M+H)⁺.

Intermediate 27AU3-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

(S)-Quinuclidin-3-ol (0.758 g, 5.96 mmol) was dissolved in DMF (15 mL)at RT with stirring. NaH, (60% dispersion in mineral oil, 458 mg, 11.46mmol) was added and the mixture allowed to stir for 15 min. Intermediate26 (1.0 g, 4.58 mmol) was added, and the mixture allowed to stirovernight. The reaction was quenched with water before beingconcentrated under reduced pressure. The crude material was purified byBiotage Isolera™ chromatography (silica gel, eluting with heptane-EtOAc,1:0 to 0:1) to afford 386 mg (23% yield) of the title compound as anoff-white powder.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 7.82 (t, J=1.3, 1H), 7.67 (d, J=1.2,1H), 7.66-7.64 (m, 1H), 7.50 (dd, J=2.3, 1.3, 1H), 4.65 (dd, J=7.3, 3.3,1H), 2.85-2.74 (m, 2H), 2.72-2.60 (m, 4H), 2.52 (d, J=0.9, 3H), 2.08 (q,J=2.9, 1H), 1.81 (dddt, J=12.5, 10.0, 5.1, 2.9, 1H), 1.70-1.52 (m, 2H),1.35 (dtd, J=11.4, 8.1, 7.6, 2.9, 1H)

LCMS (Analytical Method F) Rt=1.91 min, MS (ESIpos): m/z=326 (M+H)⁺.

Intermediate 28AU3-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid-chlorosodium (1:3)

Intermediate 27AU (386 mg, 1.04 mmol, 88%) was dissolved in EtOH (5 mL)in a sealed tube at RT with stirring and 2M NaOH (1.57 mL, 3.13 mmol)was added. The reaction was stirred at 80° C. for 5 h, followed by 100°C. for 24 h. The reaction mixture was quenched with 2M HCl (1.57 mL,3.13 mmol) before being concentrated under reduced pressure to afford449 mg (83% yield) of the title compound.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 7.87 (s, 1H), 7.57 (d, J=1.2, 1H),7.45-7.42 (m, 1H), 7.33-7.30 (m, 1H), 4.52-4.44 (m, 1H), 3.26-3.18 (m,1H), 2.84-2.59 (m, 5H), 2.49 (s, 3H), 2.05 (q, J=3.0, 1H), 1.89-1.79 (m,1H), 1.70-1.60 (m, 1H), 1.55 (dddd, J=12.5, 8.9, 6.3, 2.8, 1H),1.38-1.26 (m, 1H).

LCMS (Analytical Method A) Rt=0.93 min, MS (ESIpos): m/z=345 (M+H)⁺.

Intermediate 27AV3-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of (3R)-1-azabicyclo[2.2.2]octan-3-olhydrochloride (0.37 g, 2.24 mmol) in dry DMF (5 mL) was added NaH (60%dispersion in mineral oil, 172 mg, 4.3 mmol). After the mixture wasstirred for 15 min Intermediate 29 (0.4 g, 1.72 mmol) was added as oneportion. The resulting mixture was stirred at RT overnight. The reactionmixture was poured onto brine and extracted into EtOAc. The organiclayer was washed with brine, separated, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified byBiotage Isolera™ chromatography (silica gel, eluting with DCM-MeOH, 1:0to 4:1) to afford 374.9 mg (64% yield) of the title compound as yellowgum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.71 (t, J=1.3 Hz, 1H), 7.64(dd, J=2.3, 1.6 Hz, 1H), 7.56 (s, 1H), 7.11 (dd, J=2.4, 1.3 Hz, 1H),4.51-4.44 (m, 1H), 3.34 (ddd, J=14.3, 7.9, 2.0 Hz, 1H), 3.04-2.76 (m,7H), 2.19 (q, J=3.1 Hz, 1H), 2.01-1.93 (m, 1H), 1.79 (ddt, J=14.0, 9.6,4.3 Hz, 1H), 1.60 (dtd, J=13.4, 6.1, 3.0 Hz, 1H), 1.48-1.40 (m, 1H),1.37 (t, J=7.5 Hz, 3H).

LCMS (Analytical Method A) Rt=1.03 min, MS (ESIpos): m/z=340 (M+H)⁺.

Intermediate 28AV3-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)benzoicacid-chlorosodium (1:3)

Intermediate 27AV (375 mg, 1.11 mmol) was dissolved in EtOH (5 mL) and2M NaOH (1.7 mL) was added. The reactions were stirred at 80° C. in asealed tube for 8 h. The reaction was quenched by addition of HCl (2M,1.7 mL) and concentrated under reduced pressure to afford 602 mg(quantitative yield) of the title compound.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 7.97 (t, J=1.4 Hz, 1H), 7.65 (s, 1H),7.53-7.44 (m, 2H), 4.81-4.69 (m, 1H), 3.56-3.38 (m, 2H), 3.04-2.80 (m,6H), 2.28-2.15 (m, 1H), 2.13-1.92 (m, 1H), 1.87-1.68 (m, 2H), 1.62-1.42(m, 1H), 1.28 (t, J=7.5 Hz, 3H).

LCMS (Analytical Method A) Rt=0.94 min, MS (ESIpos): m/z=359 (M+H)⁺.

Intermediate 27AW3-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of (3S)-1-azabicyclo[2.2.2]octan-3-ol (0.29 g,2.24 mmol) in dry DMF (5 mL) was added NaH 60% dispersion in mineral oil(103 mg, 2.6 mmol). After the mixture was stirred for 15 minIntermediate 29 (0.4 g, 1.72 mmol) was added as one portion. Theresulting mixture was stirred at RT overnight. The reaction mixture waspoured onto brine and extracted into EtOAc. The organic layer was washedwith brine, separated, dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with DCM-MeOH, 1:0 to 4:1) to afford406 mg (69% yield) of the title compound as yellow gum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.71 (t, J=1.3 Hz, 1H),7.66-7.63 (m, 1H), 7.56 (s, 1H), 7.11 (dd, J=2.4, 1.3 Hz, 1H), 4.46 (dd,J=7.3, 3.4 Hz, 1H), 3.33 (ddd, J=14.4, 8.0, 2.0 Hz, 1H), 3.03-2.75 (m,7H), 2.20-2.14 (m, 1H), 2.00-1.92 (m, 1H), 1.77 (ddt, J=14.1, 9.9, 4.3Hz, 1H), 1.64-1.55 (m, 1H), 1.46-1.40 (m, 1H), 1.37 (t, J=7.5 Hz, 3H).

LCMS (Analytical Method A) Rt=1.03 min, MS (ESIpos): m/z=340 (M+H)⁺.

Intermediate 28AW3-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)benzoicacid-chlorosodium (1:3)

Intermediate 27AW (365 mg, 1.08 mmol) was dissolved in EtOH (5 mL) and2M NaOH (1.6 mL) was added. The reactions were stirred at 80° C. in asealed tube for 8 h. The reaction was quenched by addition of HCl (2M,1.6 mL) and concentrated under reduced pressure to afford 502 mg (86%yield) of the title compound.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 7.97 (t, J=1.3 Hz, 1H), 7.65 (s, 1H),7.57-7.44 (m, 2H), 4.82-4.67 (m, 1H), 3.49 (dd, J=13.6, 7.8 Hz, 1H),3.08-2.79 (m, 7H), 2.28-2.17 (m, 1H), 2.08-1.87 (m, 1H), 1.86-1.70 (m,2H), 1.61-1.43 (m, 1H), 1.28 (t, J=7.5 Hz, 3H).

LCMS (Analytical Method A) Rt=0.95 min, MS (ESIpos): m/z=359 (M+H)⁺.

Intermediate 6AX 2-methyl-2-nitropropyl 4-methylbenzenesulfonate

2-Methyl-2-nitropropan-1-ol (0.5 g, 4.2 mmol), triethylamine (0.878 ml,6.3 mmol) and trimethylamine hydrochloride (40 mg, 0.42 mmol) werestirred in DCM (10 mL), and 4-methylbenzenesulfonyl chloride (1.2 g, 6.3mmol) was added. The reaction was stirred at RT for 1.5 h. TLC (70%EtOAc in heptane) showed complete reaction, hence the reaction mixturewas treated with N,N-dimethylethane-1,2-diamine (0.28 ml, 2.52 mmol) toconsume the unreacted TsCl. The reaction mixture was washed with 1 M HCl(10 mL) then water (10 mL) before being dried over MgSO₄, filtered andconcentrated under reduced pressure to afford 1.16 g (99% yield) of thetitle compound as a yellow crystalline solid

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.77 (d, J=8.3 Hz, 2H), 7.37 (d,J=8.0 Hz, 2H), 4.28 (s, 2H), 2.47 (s, 3H), 1.60 (s, 6H).

Intermediate 27AZ Tert-butyl5-[3-cyano-5-(5-methylthiazol-2-yl)phenoxy]-2-azabicyclo[2.2.1]heptane-2-carboxylate

To a stirred solution of tert-butyl5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (254 mg, 1.19 mmol)in dry DMF (4 mL) was added NaH (60%, 55 mg, 1.37 mmol). After themixture was stirred for 90 mins, Intermediate 26 (200 mg, 0.92 mmol) wasadded to the reaction in one portion. The resulting mixture was stirredovernight at RT. The reaction was stopped and poured onto brine andextracted using ethyl acetate. The organic layer was washed with brine,separated, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified by Biotage Isolera™chromatography (basic silica gel, eluting with heptane-EtOAc, 6:2 to 0:1followed by EtOAc-MeOH, 1:0 to 4:1) to afford 388 mg (86% yield) of thetitle compound as a yellow gum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.71 (s, 1H), 7.63 (s, 1H), 7.54(d, J=1.1 Hz, 1H), 7.10 (s, 1H), 4.50 (d, J=6.1 Hz, 1H), 3.37-3.30 (m,1H), 3.07-2.98 (m, 1H), 2.54 (d, J=1.1 Hz, 3H), 1.87 (d, J=10.0 Hz, 1H),1.72-1.59 (m, 5H), 1.47 (s, 9H).

LCMS (Analytical Method A) Rt=1.47 min, MS (ESIpos): m/z=356 (M+H)⁺.

Intermediate 28AZ3-[(2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptan-5-yl)oxy]-5-(5-methylthiazol-2-yl)benzoicacid

A stirred solution of Intermediate 27AZ (388 mg, 0.94 mmol) in 2M NaOH(4.71 mL) and DMSO (4.5 mL) was heated to 110° C. for 3 hours. Aftercooling to RT the mixture was slowly acidified to pH ˜2, before beingdried using the genevac to afford the crude material in residual DMSO.Crude material was taken up in minimal MeOH and the salt was removed byfiltration. MeOH was removed and the material was purified bypreparative HPLC (Method B) to afford 49 mg (12% yield) of the titlecompound as a colourless gum.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.24 (t, J=1.4 Hz, 1H),7.65-7.58 (m, 3H), 4.63-4.54 (m, 1H), 4.30 (d, J=62.5 Hz, 1H), 3.36-3.30(m, 1H), 3.08 (dd, J=54.7, 10.4 Hz, 1H), 2.82-2.78 (m, 1H), 2.54 (d,J=1.1 Hz, 3H), 2.42-2.30 (m, 1H), 1.92 (d, J=9.9 Hz, 1H), 1.74-1.66 (m,2H), 1.48 (s, 9H).

LCMS (Analytical Method A) Rt=1.36 min, MS (ESIpos): m/z=431 (M+H)⁺.

Intermediate 27BA3-(5-methylthiazol-2-yl)-5-[2-(1,2,4-triazol-1-yl)ethoxy]benzonitrile

A solution of 2-(1H-1,2,4-triazol-1-yl)ethanol (465 mg, 4.11 mmol) anddry DMF (3 mL) was prepared. NaH (60% in mineral oil, 205 mg, 5.14 mmol)was added, and the solution was stirred for 90 mins, after whichIntermediate 26 (747 mg, 3.42 mmol) was added. The resulting mixture wasstirred over night at RT. Brine was then added to the reaction, and thereaction solution was extracted with ethyl acetate. The solution waswashed with water and the organic layer was separated and dried overNa₂SO₄, filtered and concentrated under reduced pressure. BiotageIsolera™ chromatography (silica gel, eluting with DCM-MeOH, 1:0 to 4:1)gave 604 mg (48% yield) of the title compound as a waxy solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.22 (s, 1H), 7.97 (s, 1H), 7.73(s, 1H), 7.65 (s, 1H), 7.56-7.50 (m, 1H), 7.15-7.06 (m, 1H), 4.61 (t,J=5.0 Hz, 2H), 4.44 (t, J=5.0 Hz, 2H), 2.53 (s, 3H).

LCMS (Analytical Method A) Rt=1.09 min, MS (ESIpos): m/z=333.95 (M+H)⁺.

Intermediate 28BA3-(5-methylthiazol-2-yl)-5-[2-(1,2,4-triazol-1-yl)ethoxy]benzoicacid-chlorosodium (1:3)

Intermediate 27BA (604 mg, 1.94 mmol) was dissolved in EtOH (4 mL) and2M NaOH (2.91 mL) was added. The reaction was stirred in the microwaveat 130° C. for 1 h. On completion, the reaction was quenched with 2M HCl(2.91 mL) and concentrated under reduced pressure to afford 572 mg (58%yield) of the title compound.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 8.60 (s, 1H), 8.41 (s, 2H), 7.98 (s,1H), 7.92 (s, 1H), 7.44 (s, 1H), 4.60 (t, J=5.0 Hz, 2H), 4.41 (t, J=5.0Hz, 2H). LCMS (Analytical Method A) Rt=1.00 min, MS (ESIpos): m/z=333(M+H)⁺.

Intermediate 27BC tert-butyl(4aS,7R,7aR)-7-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-octahydrocyclopenta[b]morpholine-4-carboxylate

To a stirred solution of tert-butyl(4aS,7R,7aR)-7-hydroxy-octahydrocyclopenta[b]morpholine-4-carboxylate(215 mg, 0.88 mmol) in dry DMF (3 mL) in a three-necked heat-gun-driedflask under nitrogen, was added NaH 60% dispersion in mineral oil (37mg, 0.92 mmol) and the mixture was stirred for 15 minutes beforeIntermediate 26 (161 mg, 0.74 mmol) was added as one portion.

The resulting mixture was stirred at ambient temperature for 20 h. Thereaction mixture was poured onto water and extracted with EtOAc (×2).The combined organic extracts were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified byBiotage Isolera™ chromatography (silica gel, eluting with heptane/EtOAc,1:0 to 3:2) to afford 262 mg (68% yield) of the title compound as brownoil.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.74 (t, J=1.3 Hz, 1H),7.70-7.66 (m, 1H), 7.53 (d, J=1.1 Hz, 1H), 7.19 (dd, J=2.3, 1.3 Hz, 1H),4.62 (ddd, J=9.3, 7.9, 4.6 Hz, 1H), 4.03 (ddd, J=11.6, 3.5, 1.5 Hz, 1H),3.89 (d, J=13.1 Hz, 1H), 3.69 (td, J=11.8, 2.9 Hz, 1H), 3.58 (dd,J=10.2, 7.8 Hz, 1H), 3.07-2.78 (m, 2H), 2.58-2.54 (m, 1H), 2.53 (d,J=1.0 Hz, 3H), 2.32 (dq, J=14.3, 9.3 Hz, 1H), 2.16-1.94 (m, 1H), 1.79(ddd, J=14.3, 10.6, 4.4 Hz, 1H), 1.47 (s, 9H).

LCMS (Analytical Method A) Rt=1.43 min, MS (ESIpos): m/z=442.0 (M+H)⁺.

Intermediate 28BC3-{[(4aS,7R,7aR)-4-[(tert-butoxy)carbonyl]octahydrocyclopenta[b]morpholin-7-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 27BC (258 mg, 2.01 mmol) was stirred in 2 M NaOH (2.8 mL)and DMSO (2.8 mL) at 110° C. for 3 h. The mixture was slowly acidifiedto pH ˜4 with 2 M HCl, at which point off-pink precipitate formed. Thiswas filtered and dried under vacuum filtration to afford 155 mg (58%yield) of the title compound as a pale pink solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.31 (s, 1H), 7.69-7.67 (m, 1H),7.67-7.63 (m, 1H), 7.58 (d, J=0.9 Hz, 1H), 4.68 (td, J=9.0, 4.6 Hz, 1H),4.09-3.99 (m, 1H), 3.90 (d, J=13.3 Hz, 1H), 3.72 (td, J=11.7, 2.8 Hz,1H), 3.63 (dd, J=10.1, 7.9 Hz, 1H), 3.05-2.89 (m, 2H), 2.53 (s, 3H),2.52-2.49 (m, 1H), 2.36 (dq, J=14.2, 9.1 Hz, 1H), 2.07 (dt, J=22.4, 10.3Hz, 1H), 1.84-1.74 (m, 1H), 1.47 (s, 9H)

LCMS (Analytical Method A) Rt=1.28 min, MS (ESIpos): m/z=461.1 (M+H)⁺.

Intermediate 27BD tert-butyl(4aS,7S,7aR)-7-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-octahydrocyclopenta[b]morpholine-4-carboxylate

To a stirred solution of tert-butyl(4aS,7S,7aR)-7-hydroxy-octahydrocyclopenta[b]morpholine-4-carboxylate(215 mg, 0.88 mmol) in dry DMF (3 mL) in a three-necked heat-gun-driedflask under nitrogen, was added NaH 60% dispersion in mineral oil (37mg, 0.92 mmol) and the mixture was stirred for 15 minutes beforeIntermediate 26 (161 mg, 0.74 mmol) was added as one portion. Theresulting mixture was stirred at ambient temperature for 3.5 h. Thereaction mixture was poured onto water and extracted with ethyl acetatetwice. The combined organic extracts were dried over MgSO₄, filtered,concentrated under reduced pressure and purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 3:2) toafford 338 mg (85% yield) of the title compound as pale pink solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.73 (d, J=1.2 Hz, 1H),7.69-7.64 (m, 1H), 7.52 (d, J=1.1 Hz, 1H), 7.19 (dd, J=2.3, 1.3 Hz, 1H),4.84-4.71 (m, 1H), 4.05 (ddd, J=11.6, 3.4, 1.6 Hz, 1H), 3.86 (d, J=13.5Hz, 1H), 3.69 (td, J=11.7, 2.8 Hz, 1H), 3.46 (td, J=10.5, 6.8 Hz, 1H),3.33 (dd, J=10.5, 4.6 Hz, 1H), 3.00 (ddd, J=13.6, 11.9, 3.6 Hz, 1H),2.61-2.54 (m, 1H), 2.53 (d, J=0.9 Hz, 3H), 2.32-2.20 (m, 1H), 1.88-1.72(m, 2H), 1.47 (s, 9H).

LCMS (Analytical Method A) Rt=1.40 min, MS (ESIpos): m/z=442.0 (M+H)⁺.

Intermediate 28BD3-{[(4aS,7S,7aR)-4-[(tert-butoxy)carbonyl]-octahydrocyclopenta[b]morpholin-7-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 27BD (333 mg, 0.62 mmol) was dissolved in EtOH (3 mL) and2M NaOH (1.2 mL) was added. The reaction was stirred at 80° C. for 24 h.The reaction was stopped, cooled to ambient temperature and ethanol wasremoved under reduced pressure. The resulting mixture was acidified to˜pH 4 by addition of 2M HCl, at which point a white precipitate formed.This was collected by filtration, washed with water and dried in vacuumoven to afford 244 mg (77% yield) of the title compound as an off-whitesolid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.24 (s, 1H), 7.84 (s, 1H), 7.74(s, 1H), 7.63 (s, 1H), 4.93 (t, J=5.4 Hz, 1H), 4.20-4.08 (m, 1H), 3.88(d, J=13.4 Hz, 1H), 3.78-3.68 (m, 1H), 3.52 (td, J=10.5, 6.8 Hz, 1H),3.38 (dd, J=10.6, 4.8 Hz, 1H), 3.05 (td, J=13.6, 3.6 Hz, 1H), 2.55 (s,3H), 2.54-2.47 (m, 1H), 2.37 (dd, J=20.9, 10.1 Hz, 1H), 1.90-1.70 (m,2H), 1.47 (s, 9H).

LCMS (Analytical Method A) Rt=1.26 min, MS (ESIpos): m/z=461.1 (M+H)⁺.

Intermediate 83 (2S)-2-[(benzyloxy)methyl]-1,4-dioxane

To a solution of (2R)-3-(benzyloxy)propane-1,2-diol (2 g, 11 mmol) andtetra-n-butylammonium bromide (0.71 g, 2.2 mmol) in dichloroethane (52mL) was added sodium hydroxide (26.3 g, 0.66 mol) as a solution in water(25 mL). The reaction mixture was then stirred at 50° C. for 16 h.Further dichloroethane (52 mL) and sodium hydroxide (26.3 g, 0.66 mol)as a solution in water (25 mL) was added and the reaction mixturestirred at 50° C. for a further 48 h. The reaction mixture was filteredunder vacuum, washing with ethyl acetate. The filtrate was diluted withwater and the layers separated. The organic layer was further washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 1:1) toafford 1.25 g (54% yield) of the title compound as colourless oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.40-7.27 (m, 5H), 4.55 (s, 2H),3.86-3.57 (m, 6H), 3.52-3.37 (m, 3H).

Intermediate 84 (2S)-1,4-dioxan-2-ylmethanol

To a solution of Intermediate 83 (1.25 g, 4.74 mmol) in ethanol (20 mL)was added palladium, 10% on carbon (192 mg) and the reaction mixturestirred under an atmosphere of hydrogen for 18 h. The reaction mixturewas filtered through a plug of Celite®, washing with EtOAc, andconcentrated under reduced pressure to afford 630 mg (89% yield) of thetitle compound as pale yellow oil.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 3.85-3.67 (m, 5H), 3.66-3.57 (m,2H), 3.55 (dd, J=11.7, 5.9 Hz, 1H), 3.46 (dd, J=11.1, 10.0 Hz, 1H), 1.75(s, 1H).

Intermediate 27BE3-[(2R)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of Intermediate 84 (250 mg, 1.76 mmol) in dry DMF(7 mL) was added NaH 60% dispersion in mineral oil (88 mg, 2.20 mmol).After the mixture was stirred for 15 min, Intermediate 26 (385 mg, 1.76mmol) was added as one portion. The resulting mixture was stirred atambient temperature for 1.5 h. The reaction mixture was then poured ontobrine and extracted into EtOAc. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude material was purified by Biotage Isolera™ chromatography (silicagel, eluting with heptane-EtOAc, 1:0 to 20:9) to afford 460 mg (82%yield) of the title compound as an off-white solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.75 (s, 1H), 7.71-7.67 (m, 1H),7.55-7.49 (m, 1H), 7.18 (dd, J=2.3, 1.2 Hz, 1H), 4.11-4.05 (m, 1H),4.05-3.98 (m, 2H), 3.93-3.85 (m, 2H), 3.82 (td, J=11.7, 11.1, 2.6 Hz,1H), 3.78-3.72 (m, 1H), 3.68 (td, J=11.5, 3.2 Hz, 1H), 3.56 (dd, J=11.4,9.3 Hz, 1H), 2.54 (s, 3H)

LCMS (Analytical Method A) Rt=1.17 min, MS (ESIpos): m/z=317.0 (M+H)⁺.

Intermediate 28BE3-[(2R)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 27BE (455 mg, 1.44 mmol) was dissolved in EtOH (7 mL) and2M NaOH (2.9 mL) was added. The reaction was stirred in a microwave at130° C. for 1 h. The reaction was stopped, cooled to ambient temperatureand ethanol was removed under reduced pressure. The resulting mixturewas acidified to ˜pH 4 by addition of 2M HCl, at which point a whiteprecipitate formed. This was collected by filtration, washed with waterand dried in vacuum oven overnight to afford 480 mg (99% yield) of thetitle compound as an off-white solid.

¹H NMR (500 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.69 (s, 1H), 7.67 (s,1H), 7.59 (s, 1H), 4.17-4.10 (m, 1H), 4.09-4.00 (m, 2H), 3.97-3.86 (m,2H), 3.83 (td, J=11.7, 11.2, 2.5 Hz, 1H), 3.77 (d, J=11.0 Hz, 1H), 3.69(td, J=11.3, 3.0 Hz, 1H), 3.59 (t, J=10.7 Hz, 1H), 2.54 (s, 3H).

LCMS (Analytical Method A) Rt=1.05 min, MS (ESIpos): m/z=336.0 (M+H)⁺.

Intermediate 85 (2R)-2-[(benzyloxy)methyl]-1,4-dioxane

To a solution of (2S)-3-(benzyloxy)propane-1,2-diol (0.8 g, 4.4 mmol)and tetra-n-butylammonium bromide (283 mg, 0.88 mmol) in dichloroethane(21 mL) was added sodium hydroxide (10.5 g, 0.26 mol) as a solution inwater (10 mL). The reaction mixture was then stirred at 50° C. for 16 h.Further dichloroethane (21 mL) and sodium hydroxide (10.5 g, 0.26 mol)as a solution in water (10 mL) was added and the reaction mixturestirred at 50° C. for a further 48 h. The reaction mixture was filteredunder vacuum, washing with ethyl acetate. The filtrate was diluted withwater and the layers separated. The organic layer was further washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 1:1 to 1:1) toafford 560 mg (60% yield) of the title compound as colourless oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.40-7.27 (m, 5H), 4.55 (s, 2H),3.86-3.60 (m, 6H), 3.52-3.38 (m, 3H).

Intermediate 86 (2R)-1,4-Dioxan-2-ylmethanol

To a solution of Intermediate 85 (560 mg, 2.47 mmol) in ethanol (10 mL)was added palladium, 10% on carbon (100 mg) and the reaction mixture wasstirred under an atmosphere of hydrogen for 18 h. The solution wasfiltered through a plug of Celite®, washing with EtOAc, and concentratedunder reduced pressure to afford 260 mg (89% yield) of the titlecompound as pale yellow oil.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 3.87-3.66 (m, 5H), 3.65-3.58 (m,2H), 3.54 (dd, J=11.7, 5.9 Hz, 1H), 3.46 (t, J=10.6 Hz, 1H), 1.95 (s,1H).

Intermediate 27BF3-[(2S)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of Intermediate 86 (250 mg, 2.12 mmol) in dry DMF(7 mL) was added NaH 60% dispersion in mineral oil (88 mg, 2.20 mmol).After the mixture was stirred for 15 min, Intermediate 26 (385 mg, 1.76mmol) was added as one portion. The resulting mixture was stirred atambient temperature for 2.5 h. The reaction mixture was then poured ontobrine and extracted into ethyl acetate. The organic layer was washedwith brine, separated, dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 20:9) toafford 400 mg (72% yield) of the title compound as pale yellow solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.75 (s, 1H), 7.69 (s, 1H), 7.54(s, 1H), 7.18 (s, 1H), 4.11-4.05 (m, 1H), 4.05-3.98 (m, 2H), 3.92-3.86(m, 2H), 3.82 (td, J=11.7, 11.2, 2.6 Hz, 1H), 3.76 (d, J=12.1 Hz, 1H),3.68 (td, J=11.3, 3.2 Hz, 1H), 3.56 (dd, J=11.4, 9.3 Hz, 1H), 2.54 (s,3H).

LCMS (Analytical Method A) Rt=1.17 min, MS (ESIpos): m/z=317.0 (M+H)⁺.

Intermediate 28BF3-[(2S)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 27BF (395 mg, 1.25 mmol) was dissolved in ethanol (6 mL)and 2M NaOH (2.5 mL) was added. The reaction was stirred in a microwaveat 130° C. for 2 h. The reaction was stopped, cooled to ambienttemperature and ethanol was removed under reduced pressure. Theresulting mixture was acidified to ˜pH 4 by addition of 2M HCl, at whichpoint a white precipitate formed. This was collected by filtration,washed with water and dried in vacuum oven overnight to afford 380 mg(89% yield) of the title compound as an off-white solid.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 13.32 (s, 1H), 7.98 (s, 1H), 7.65 (s,1H), 7.61 (s, 1H), 7.49 (s, 1H), 4.15-4.04 (m, 2H), 3.93-3.86 (m, 1H),3.84 (d, J=11.4 Hz, 1H), 3.80-3.74 (m, 1H), 3.71-3.59 (m, 2H), 3.55-3.47(m, 1H), 3.47-3.40 (m, 1H)

LCMS (Analytical Method A) Rt=1.05 min, MS (ESIpos): m/z=336.0 (M+H)⁺.

Intermediate 34 tert-butyl3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}carbamoyl)phenoxy]azetidine-1-carboxylate

To a solution of Intermediate 5AD (185 mg, 0.47 mmol), IntermediateXVIII (130 mg, 0.57 mmol) and DIPEA (248 μL, 1.42 mmol) in DCM (1 mL)was added HATU (270 mg, 0.71 mmol) and the resulting mixture stirred atRT for 2 h. DCM (1 mL) was added and the crude reaction product washedwith water (1 mL). The organic phase was separated, dried over MgSO₄,filtered and concentrated under reduced pressure. The crude material waspurified by Biotage Isolera™ chromatography (silica gel, eluting withheptane-EtOAc, 9:1 to 1:9) to give 248 mg (63% yield) of the titlecompound as yellow oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 7.91 (t, J=1.4 Hz, 1H), 7.81 (s,1H), 7.76 (s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.42(dd, J=2.4, 1.4 Hz, 1H), 5.59 (m, 1H), 5.07-4.92 (m, 1H), 4.35 (dd,J=9.7, 6.4 Hz, 2H), 4.01 (dd, J=9.5, 3.7 Hz, 2H), 2.52 (d, J=1.1 Hz,3H), 1.75 (d, J=7.0 Hz, 3H), 1.44 (s, 9H). LCMS (Analytical Method A)Rt=1.49 min, MS (ESIpos): m/z=508.1 (M+H)⁺.

In analogy to the procedure described for Intermediate 34, the followingIntermediates were prepared using HATU and the appropriate carboxylicacid and amine starting materials.

Int. Structure Name Analytical Data 35

Tert-butyl 4-[3- ({(1R)-1-[2- (difluoromethyl) pyrimidin-5-yl]ethyl}carbamoyl)- 5-(5-methyl-1,3- thiazol-2-yl) phenoxy]piperidine-1-carboxylate ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.90 (s, 2H), 7.82(s, 1H), 7.55-7.50 (m, 2H), 7.42-7.38 (m, 1H), 6.79-6.52 (m, 2H), 5.35(m, 1H), 4.61 (tt, J = 7.3, 3.5 Hz, 1H), 3.75-3.66 (m, 2H), 3.39- 3.30(m, 2H), 2.53 (d, J = 1.0 Hz, 3H), 1.98-1.91 (m, 2H), 1.80- 1.68 (m,5H), 1.47 (s, 9H). LCMS (Analytical Method A) Rt = 1.30 min, m/z = 518(M-tBu)⁺. 55

tert-butyl (3-endo)- 3-[3-(5-methyl-1,3- thiazol-2-yl)-5- ({(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl}carbamoyl) phenoxy]-8-azabicyclo[3.2.1] octane-8- carboxylate ¹HNMR (250 MHz, Chloroform-d): δ[ppm] 8.93 (s, 2H), 7.82-7.74 (m, 1H), 7.56-7.49 (m, 1H), 7.44 (s, 1H),7.31 (d, J = 1.5 Hz, 1H), 6.70 (d, J = 6.5 Hz, 1H), 5.36 (s, 1H),4.77-4.69 (m, 1H), 4.31-4.09 (m, 2H), 2.57-2.49 (m, 3H), 2.35- 1.88 (m,8H + 1H impurity), 1.72 (d, J = 7.1 Hz, 3H), 1.47 (s, 9H). LCMS(Analytical Method A) Rt = 1.45 min, MS (ESIpos) m/z = 618 (M + H)⁺. 64

Tert-butyl (3-exo)- 3-[3-(5-methyl-1,3- thiazol-2-yl)-5- ({(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl}carbamoyl) phenoxy]-8-azabicyclo[3.2.1] octane-8- carboxylate ¹H NMR (500 MHz, Chloroform-d):δ [ppm] 8.86 (s, 2H), 7.77 (s, 1H), 7.47-7.41 (m, 2H), 7.35-7.31 (m,1H), 6.58 (d, J = 6.4 Hz, 1H), 5.28 (m, 1H), 4.73 (td, J = 10.6, 5.4 Hz,1H), 4.38-4.11 (m, 2H), 2.47 (d, J = 1.1 Hz, 3H), 2.15- 2.02 (m, 2H),2.00-1.93 (m, 2H), 1.82-1.60 (m, 7H), 1.49 (s, 9H). 72

3-{[3-hydroxybutan- 2-yl]oxy}-5-(5- methyl-1,3-thiazol-2-yl)-N-{(1S)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide,as a mixture of trans isomers ¹H NMR (250 MHz, Chloroform-d): δ [ppm]8.94 (s, 2H), 7.79 (s, 1H), 7.55-7.43 (m, 2H), 7.35 (s, 1H), 6.92 (d, J= 6.6 Hz, 1H), 5.36 (m, 1H), 4.45 (m, 1H), 4.04 (s, 1H), 2.79 (s, 6H),2.53 (s, 3H), 1.71 (d, J = 7.1 Hz, 4H), 1.32-1.23 (m, 6H). LCMS(Analytical Method D) Rt = 4.22 min, MS (ESIpos) m/z = 481 (M + H)⁺. 79

tert-Butyl- (4aS,7R,7aR)-7-[3- (5-methyl-1,3- thiazol-2-yl)-5-({(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}carbamoyl) phenoxy]hexahydrocyclopenta [b][1,4] oxazine-4(4aH)- carboxylate ¹H NMR (500MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.90-7.82 (m, 1H), 7.55 (s,1H), 7.53-7.49 (m, 1H), 7.40 (s, 1H), 6.70 (d, J = 6.3 Hz, 1H), 5.35 (m,1H), 4.65 (tt, J = 9.1, 4.6 Hz, 1H), 4.02 (d, J = 11.5 Hz, 1H), 3.89 (d,J = 12.0 Hz 1H), 3.70 (t, J = 11.5 Hz, 1H), 3.59 (dd, J = 10.1, 7.9 Hz,1H), 3.05-2.87 (m, 2H), 2.51 (s, 3H), 2.49-2.45 (m, 1H), 2.43-2.26 (m,1H), 2.05 (m, 1H), 1.76 (tt, J = 9.4, 4.6 Hz, 1H), 1.70 (d, J = 7.1 Hz,3H), 1.47 (s, 9H). LCMS (Analytical Method A) Rt = 1.41 min, MS(ESIpos): m/z = 634.2 (M + H)⁺. 81

tert-Butyl- (4aS,7S,7aR)-7-[3- (5-methyl-1,3- thiazol-2-yl)-5-({(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}carbamoyl) phenoxy]hexahydrocyclopenta [b][1,4] oxazine-4(4aH)- carboxylate ¹H NMR (500MHz, Chloroform-d): δ [ppm] 8.93 (d, J = 3.6 Hz, 2H), 7.90 (d, J = 3.9Hz, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 6.73 (d, J = 6.2 Hz,1H), 5.34 (m, 1H), 4.84 (m, 1H), 4.08 (d, J = 11.7 Hz, 1H), 3.87 (d, J =13.6 Hz, 1H) 3.70 (t, J = 11.6 Hz, 1H), 3.56-3.42 (m, 1H), 3.33 (dd, J =10.1, 4.3 Hz, 1H), 3.02 (td, J = 13.6, 3.6 Hz, 1H), 2.56-2.52 (m, 4H),2.27 (t, J = 15.1 Hz, 1H), 1.85-1.75 (m, 2H), 1.71 (dd, J = 7.1, 1.8 Hz,3H), 1.47 (s, 9H) LCMS (Analytical Method A) Rt = 1.37 min, MS (ESIpos):m/z = 634.2 (M + H)⁺. 93

3-[(-3- hydroxybutan-2- yl)oxy]-5-(5-methyl- 1,3-thiazol-2-yl)-N-[(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamide, as amixture of 2 cis isomers LCMS (MSQ1, 7 min) 82% @ Rt = 3.11 min, MS(ESIpos): m/z = 481.1 (M + H)+.

Intermediate 33 Tert-butyl3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]azetidine-1-carboxylate

Intermediate 5AD (205.6 mg, 0.527 mmol), Intermediate VI (121 mg, 0.632mmol) and DIPEA (367 μL, 2.1 mmol) were combined in DCM (5 mL) and T3P(470 μL, 0.79 mmol) was added. The reaction mixture was stirred at RTfor 2 h, then washed with saturated NaHCO₃ (5 mL). The layers wereseparated, and the aqueous layer extracted with DCM (2×5 mL). Thecombined organics were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 4:1 to 1:4) toafford 226 mg (74% yield) of the title compound as colourless solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.90 (s, 1H), 7.54(s, 1H), 7.40 (s, 1H), 7.22 (s, 1H), 6.69 (d, J=6.5 Hz, 1H), 5.36 (m,1H), 4.98 (ddd, J=10.4, 6.4, 4.0 Hz, 1H), 4.35 (dd, J=9.6, 6.5 Hz, 2H),4.00 (dd, J=9.7, 3.7 Hz, 2H), 2.54 (s, 3H), 1.72 (d, J=7.2 Hz, 3H), 1.45(s, 9H).

LCMS (Analytical Method A) Rt=1.33 min, MS (ESIpos): m/z=508 (M-tBu)⁺.

In analogy to the procedure described for Intermediate 33, the followingIntermediates were prepared using T3P and the appropriate carboxylicacid and amine starting materials.

Int. Structure Name Analytical Data 37

Tert-butyl (3S)-3-[3- (5-methyl-1,3- thiazol-2-yl)-5-({(1R)- 1-[2-(trifluoromethyl) pyrimidin-5-yl] ethyl}carbamoyl) phenoxy]pyrrolidine-1-carboxylate ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.88 (s, 2H), 7.87(d, J = 17.1 Hz, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 6.70 (s,1H), 5.29 (m, 1H), 4.96 (s, 1H), 3.62-3.39 (m, 4H), 2.48 (s, 3H), 2.11(d, J = 9.2 Hz, 2H), 1.66 (d, J = 7.2 Hz, 3H), 1.39 (s, 9H). LCMS(Analytical Method D) Rt = 4.84 min, MS (ESIpos): m/z = 578.15 (M + H)⁺.41

Tert-butyl 4-[3-(5- methyl-1,3-thiazol-2- yl)-5-({(1R)-1-[6-(trifluoromethyl) pyridazin-3- yl]ethyl}carbamoyl) phenoxy]piperidine-1-carboxylate ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.87 (t, J = 1.4Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.58 (dd, J= 2.4, 1.5 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.50-7.46 (m, 1H), 7.42(dd, J = 2.3, 1.5 Hz, 1H), 5.60 (m, 1H), 4.62 (tt, J = 7.1, 3.4 Hz, 1H),3.75-3.66 (m, 2H), 3.40-3.31 (m, 2H), 2.53 (d, J = 1.1 Hz, 3H),2.01-1.90 (m, 2H), 1.76 (d, J = 7.0 Hz, 5H), 1.47 (s, 9H). LCMS(Analytical Method A) Rt = 1.55 min, MS (ESIpos): m/z = 592.2 (M + H)⁺.50

Tert-butyl 3-fluoro-4- [3-(5-methyl-1,3- thiazol-2-yl)-5-{[(1R)- 1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl]carbamoyl} phenoxy]piperidine-1-carboxylate, as a mixture of trans isomers ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.86 (d, J = 1.4 Hz, 1H), 7.60-7.56(m, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.44 (t, J = 3.5 Hz, 1H), 6.64 (d, J= 6.5 Hz, 1H), 5.36 (m, 1H), 4.59 (m, 2H), 3.68-2.97 (m, 4H), 2.54 (d, J= 1.1 Hz, 3H), 2.20-2.10 (m, 1H), 1.76 (s, 1H), 1.72 (d, J = 7.1 Hz,3H), 1.48 (s, 9H). LCMS (Analytical Method A) Rt = 1.36 min, MS(ESIpos): m/z = 554 (M-tBu)⁺. 66

Tert-butyl 4-[3-(5- methyl-1,3-thiazol-2- yl)-5-({(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl}carbamoyl) phenoxy]-2-(trifluoromethyl) piperidine- 1-carboxylate, as a mixture of transisomers ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (d, J = 1.2 Hz,2H), 7.84 (d, J = 1.4 Hz, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.51 (s, 1H),7.36 (q, J = 2.1 Hz, 1H), 6.61 (d, J = 6.5 Hz, 1H), 5.35 (m, 1H),4.89-4.68 (m, 2H), 4.11-4.04 (m, 1H), 3.37 (t, J = 12.7 Hz, 1H), 2.54(d, J = 1.0 Hz, 3H), 2.36 (dd, J = 15.5, 2.1 Hz, 1H), 2.08 (td, J = 8.0,7.5, 4.3 Hz, 1H), 2.01 (d, J = 14.0 Hz, 1H), 1.90-1.78 (m, 1H), 1.73 (d,J = 7.2 Hz, 3H), 1.49 (s, 9H). LCMS (Analytical Method A) Rt = 1.49 min,MS (ESIpos): m/z = 604.00 (M-tBu)⁺. 68

3-(2-Methyl-2- nitropropoxy)-5-(5- methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide 1HNMR (500 MHz, Chloroform- d): δ [ppm] 8.96 (s, 2H), 8.02 (s, 1H),7.56-7.54 (m, 1H), 7.51- 7.48 (m, 1H), 7.41-7.38 (m, 1H), 6.95 (s, 1H),5.36 (m, 1H), 4.37 (q, J = 9.8 Hz, 2H), 2.55 (d, J = 0.9 Hz, 3H),1.80-1.68 (m, 9H). LCMS (Analytical Method A) Rt = 1.44 min, MS(ESIpos): m/z = 510.0 (M + H)⁺. 69

Tert-butyl (1-{[3-(5- methyl-1,3-thiazol-2- yl)-5-({(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl}carbamoyl) phenoxy]methyl}cyclopropyl) carbamate 1H NMR (250 MHz, Chloroform-d) δ 8.95 (s, 2H),7.84 (s, 1H), 7.51- 7.40 (m, 3H), 6.96 (d, J = 6.6 Hz, 1H), 5.39 (m,1H), 5.24 (s, 1H), 4.05 (s, 2H), 2.52 (d, J = 0.9 Hz, 3H), 1.73 (d, J =7.2 Hz, 3H), 1.42 (s, 9H), 0.96-0.87 (m, 4H). LCMS (Analytical Method A)100% @ Rt = 1.34 min, MS (ESIpos): m/z = 578.1 (M + H)⁺. 73

Tert-butyl 5-[3-(5- methylthiazol-2-yl)- 5-[[(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl]carbamoyl] phenoxy]-2-azabicyclo[2.2.1] heptane-2-carboxylate ¹H NMR (500 MHz, Chloroform-d):δ [ppm] 8.92 (s, 2H), 7.81 (s, 1H), 7.50 (d, J = 1.2 Hz, 1H), 7.47- 7.44(m, 1H), 7.33 (br.s, 1H), 6.86 (d, J = 5.7 Hz, 1H), 5.39- 5.32 (m, 1H),4.53-4.47 (m, 1H), 4.25 (m, 1H), 3.28 (dd, J = 10.3, 3.6 Hz, 1H),3.02-2.95 (m, 1H), 2.75 (br.s, 1H), 2.52 (d, J = 1.0 Hz, 3H), 2.33-2.20(m, 1H), 1.89-1.83 (m, 1H), 1.70 (d, J = 7.2 Hz, 3H), 1.68-1.60 (m, 2H),1.45 (s, 9H). LCMS (Analytical Method A) Rt = 1.53 min, MS (ESIpos): m/z= 548 (M + H)⁺.

Intermediate 353-(Azetidin-3-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of Intermediate 33 (226 mg, 0.40 mmol) dissolved in DCM (5mL) was added TFA (0.3 mL, 4.0 mmol) and the reaction stirred at RTuntil gas evolution ceased. The reaction mixture was neutralised withsaturated NaHCO₃ solution, producing a precipitate. This was collectedby filtration under reduced pressure and dried in the vacuum oven toafford 188.7 mg (quantitative yield) of the title compound as whitepowder.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.42-9.09 (m, 3H), 7.94 (s, 1H), 7.65(s, 1H), 7.42 (m, 2H), 5.30 (m, 1H), 5.17-4.92 (m, 1H), 4.03-3.76 (m,2H), 3.62-3.51 (m, 2H), 1.62 (d, J=7.1 Hz, 3H).

LCMS (Analytical Method A) Rt=0.94 min, MS (ESIpos): m/z=464.0 (M+H)⁺.

Intermediate 363-(azetidin-3-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

To a solution of Intermediate 34 (248 mg, 0.30 mmol, 68% purity) in DCM(1 mL) was added TFA (0.1 mL) then stirred for 4 h. The reaction mixturewas concentrated under reduced pressure and the residue taken up inwater and basified to pH ˜4 with 10 M NaOH solution to give an off-whiteprecipitate that was collected by filtration to afford 81 mg (53% yield)of the title compound as an off-white powder.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.35 (d, J=6.9 Hz, 1H), 8.24 (d,J=8.8 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 7.43(d, J=11.9 Hz, 2H), 5.52-5.45 (m, 1H), 5.17 (q, J=5.8 Hz, 1H), 3.92 (t,J=7.6 Hz, 2H), 3.65-3.61 (m, 2H), 1.66 (d, J=7.1 Hz, 3H).

LCMS (Analytical Method A) Rt=0.88 min, MS (ESIpos) m/z 464 (M+H⁺).

In analogy to the procedure described for Intermediate 36, the followingIntermediates were prepared using TFA and the appropriate N-Bocprotected amine starting materials.

Int. Structure Name Analytical Data 40

3-(5-methyl-1,3- thiazol-2-yl)-5- [piperidin-3-yloxy]- N-{(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide, as a mixture of 2diastereoisomers ¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.17 (d, J = 7.1 Hz,1H), 9.11 (s, 2H), 7.91 (s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.59-7.55 (m,1H), 7.54-7.50 (m, 1H), 5.29 (m, 1H), 4.48 (dt, J = 7.5, 3.9 Hz, 1H),3.15 (d, J = 12.2 Hz, 1H), 2.82 (dt, J = 11.8, 4.4 Hz, 1H), 2.62 (m,2H), 2.02 (s, 1H), 1.77-1.67 (m, 1H), 1.61 (d, J = 7.1 Hz, 3H), 1.49(ddt, J = 13.1, 9.3, 5.1 Hz, 1H). 43

3-(5-methyl-1,3- thiazol-2-yl)-5- (piperidin-4-yloxy)- N-{(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz,Chloroform-d) δ 8.93 (s, 2H), 7.81 (s, 1H), 7.54- 7.49 (m, 2H),7.41-7.37 (m, 1H), 6.73 (d, J = 6.9 Hz, 1H), 5.35 (m, 1H), 4.51 (tt, J =8.4, 3.8 Hz, 1H), 3.17-3.11 (m, 2H), 2.80-2.72 (m, 2H), 2.53 (s, 3H),2.08-2.00 (m, 2H), 1.95 (s, 1H), 1.74-1.64 (m, 5H). LCMS (AnalyticalMethod D) Rt = 3.12, MS (ESIpos): m/z = 493 (M + H)⁺. 46

3-(2- azaspiro[3.3]hept-6- yloxy)-5-(5-methyl- 1,3-thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide 1H NMR(500 MHz, DMSO-d6): δ [ppm] 9.22 (d, J = 7.1 Hz, 1H), 9.11 (s, 2H), 7.93(s, 1H), 7.66- 7.62 (m, 1H), 7.41 (d, J = 10.2 Hz, 2H), 5.29 (m, 1H),4.78 (p, J = 6.7 Hz, 1H), 4.03 (s, 2H), 3.93 (s, 2H), 3.17 (s, 3H), 2.81(dd, J = 12.4, 6.8 Hz, 2H), 2.30 (dd, J = 13.2, 6.6 Hz, 2H), 1.61 (d, J= 7.1 Hz, 3H). LCMS (Analytical Method D) Rt = 3.20 min, MS (ESIpos):m/z = 504 (M + H)⁺. 51

3-[(3- Fluoropiperidin-4- yl)oxy]-5-(5-methyl- 1,3-thiazol-2-yl)-N-[(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl]benzamide, as amixture of trans isomers ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94(s, 2H), 7.86 (d, J = 1.5 Hz, 1H), 7.61-7.57 (m, 1H), 7.53 (d, J = 1.2Hz, 1H), 7.45 (s, 1H), 6.64 (d, J = 5.8 Hz, 1H), 5.35 (q, J = 7.1 Hz,1H), 4.66-4.49 (m, 2H), 3.44-3.33 (m, 1H), 3.05 (d, J = 13.2 Hz, 1H),2.88 (dd, J = 13.0, 7.4 Hz, 1H), 2.74 (dd, J = 12.6, 9.3 Hz, 1H), 2.54(d, J = 1.0 Hz, 3H), 2.17 (d, J = 10.7 Hz, 1H), 1.71 (t, J = 7.3 Hz,4H). LCMS (Analytical Method D) Rt = 3.28 min, MS (ESIpos): m/z = 510.0(M + H)⁺. 67

3-(5-methyl-1,3- thiazol-2-yl)-5- {[(2R,4S)-2- (trifluoromethyl)piperidin-4-yl]oxy}- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide, as a mixture of cis isomers ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.86 (d, J = 1.4 Hz, 1H), 7.56-7.50(m, 2H), 7.43-7.37 (m, 1H), 6.62 (d, J = 5.3 Hz, 1H), 5.35 (m, 1H), 4.44(tt, J = 9.7, 4.2 Hz, 1H), 3.33- 3.22 (m, 2H), 2.78 (t, J = 11.9 Hz,1H), 2.54 (d, J =1 .0 Hz, 3H), 2.33 (dtt, J = 9.7, 4.7, 2.3 Hz, 1H),2.23-2.15 (m, 1H), 1.72 (d, J = 7.2 Hz, 3H), 1.62-1.56 (m, 2H). LCMS(Analytical Method F) Rt = 2.59 min, MS (ESIpos): m/z = 560 (M + H)⁺. 70

3-[(1- Aminocyclopropyl) methoxy]-5-(5- methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamideLCMS (Analytical Method A) Rt = 0.97 min, MS (ESIpos): m/z = 478 (M +H)⁺. 74

3-(2-azabicyclo [2.2.1]heptan- 5-yloxy)-5-(5- methylthiazol-2-yl)-N-[(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl]benzamide LCMS(Analytical Method A) Rt = 0.95 min, MS (ESIpos): m/z = 504.3 (M + H)⁺.76

3-[(1R,3S,5S)-8- azabicyclo[3.2.1] octan-3-yloxy]-5-(5-methyl-1,3-thiazol- 2-yl)-N-[(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl]benzamide Used in the next step crude 77

3-[(1R,3R,5S)-8- azabicyclo[3.2.1] octan-3-yloxy]-5-(5-methyl-1,3-thiazol- 2-yl)-N-[(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl]benzamide Used in the next step crude 80

3-(5-methyl-1,3- thiazol-2-yl)-5- [(4aS,7R,7aR)- octahydrocyclopenta[b][1,4]oxazin-7- yloxy]-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H),7.90-7.82 (m, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 6.68 (d, J= 4.8 Hz, 1H), 5.35 (m, 1H), 4.68 (dq, J = 9.5, 5.5 Hz, 1H), 3.97 (d, J= 11.4 Hz, 1H), 3.72 (t, J = 11.3 Hz, 1H), 3.54 (t, J = 8.8 Hz, 1H),3.05- 2.87 (m, 2H), 2.74 (td, J = 11.1, 6.6 Hz, 1H), 2.53 (s, 3H), 2.43-2.32 (m, 1H), 1.93-1.84 (m, 1H), 1.81-1.73 (m, 2H), 1.70 (d, J = 7.1 Hz,4H). LCMS (Analytical Method A) Rt = 0.98 min, MS (ESIpos): m/z = 534.1(M + H)⁺. 82

3-(5-methyl-1,3- thiazol-2-yl)-5- [(4aS,7S,7aR)- octahydrocyclopenta[b][1,4]oxazin-7- yloxy]-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (d, J =3.5 Hz, 2H), 7.85 (d, J = 3.9 Hz, 1H), 7.57 (s, 1H), 7.52-7.48 (m, 1H),7.41 (s, 1H), 6.70 (d, J = 6.0 Hz, 1H), 5.34 (m, 1H), 4.85 (q, J = 4.8Hz, 1H), 4.03 (d, J = 11.6 Hz, 1H), 3.74 (t, J = 11.8 Hz, 1H), 3.32 (dd,J = 9.8, 3.7 Hz, 1H), 3.30-3.20 (m, 1H), 3.06 (td, J = 12.1, 3.2 Hz,1H), 2.94 (d, J = 11.7 Hz, 1H), 2.53 (s, 3H), 2.32-2.22 (m, 1H), 2.02-1.91 (m, 1H), 1.89-1.77 (m, 1H), 1.70 (dd, J = 7.1, 2.2 Hz, 3H),1.50-1.34 (m, 1H). LCMS (Analytical Method A) Rt = 0.97 min, MS(ESIpos): m/z = 534.1 (M + H)⁺.

Intermediate 6AY 1,1-Dioxidotetrahydro-2H-thiopyran-4-yl4-methylbenzenesulfonate

A mixture of tetrahydro-2H-thiopyran-4-ol 1,1-dioxide (660 mg, 4.39mmol), 4-methylbenzenesulfonyl chloride (922 mg, 4.83 mmol), TEA (920μl, 6.6 mmol), trimethylamine hydrochloride (42.0 mg, 439 μmol) in DCM(5.4 mL) was stirred at RT until complete conversion. DCM and water wereadded and the layers separated. The organic layer was evaporated todryness under reduced pressure and the residue was purified by columnchromatography to give 1.03 g (77% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 0.16-0.84 (m, 1 H) 1.99-2.18 (m, 4 H)2.43 (s, 3 H) 3.01-3.24 (m, 4 H) 4.83 (dt, 1 H) 7.49 (d, 2 H) 7.85 (d, 2H).

Intermediate 4AZ Methyl3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of Intermediate 3 (519 mg, 2.08 mmol), Intermediate 6AY (951mg, 3.13 mmol), Cs₂CO₃ (1.02 g, 3.13 mmol) in DMF (15 mL) was stirred at90° C. until complete conversion. The mixture was evaporated to drynessunder reduced pressure and the residue purified by column chromatography(silica gel, hexane/EE gradient) to give 680 mg (86% yield) of the titlecompound.

LCMS, method 1, rt: 1.10 min, MS ES+ m/z=382 (M+H)⁺.

Intermediate 5AZ3-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

A mixture of Intermediate 4AZ (680 mg, 1.78 mmol), an aqueousNaOH-solution (356 mg, 8.91 mmol, 2M) and MeOH (50 mL) was stirred at RTuntil complete conversion

The solvent was evaporated under reduced pressure and an aqueousHCl-solution (2M) was added to adjust the pH-value to pH: 6. The aqueouslayer was separated and the organic layer was evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography (silica gel) to give 288 mg (44% yield) of the titlecompound.

LCMS, method 1, rt: 0.92 min, MS ES+ m/z=368 (M+H)⁺.

Intermediate 4BA Methyl3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

A mixture of Intermediate 8 (950 mg, 2.73 mmol),2-bromo-5-ethyl-1,3-thiazole (681 mg, 3.55 mmol),[1,1,-Bis-(diphenylphosphino)-ferrocer]-palladium(II) dichloride (334mg, 409 μmol), and K₂CO₃ (6.5 ml, 1.0 M, 6.5 mmol) in THF (45 mL) wasstirred under reflux until complete conversion and evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography (silica gel, hexane/EE/MeOH gradient) to give 265 mg (29%yield) of the title compound.

LCMS, method 1, rt: 1.33 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 5BA3-(5-Ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid

A solution of intermediate 4BA (265 mg, 94% purity, 780 μmol) in MeOH (5mL), THF (5 mL) and an aqueous NaOH-solution (780 μl, 2.0 M, 1.6 mmol)was stirred at

RT until complete conversion. Water was added and the pH-value adjustedto pH: 2. The aqueous phase was extracted with EE, the combined organiclayers dried with Na₂SO₄, filtered and evaporated to dryness underreduced pressure to give 252 mg (100% yield) of the title compound whichwas used without further purification.

LCMS, method 1, MS ES+ m/z=320 (M+H)⁺.

Intermediate 4BB Methyl3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

A mixture of Intermediate 8 (870 mg, 2.50 mmol),2-chloro-5-cyclobutyl-1,3-thiazole (564 mg, 3.25 mmol),[1,1,-Bis-(diphenylphosphino)-ferrocer]-palladium(II) dichloride (306mg, 375 μmol) and K₂CO₃ (6.0 ml, 1.0 M, 6.0 mmol) in THF (41 mL) wasstirred under reflux until complete conversion and evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography (silica gel, hexane/EE gradient) to give 390 mg (43%yield) of the title compound.

LCMS, method 1, rt: 1.46 min, MS ES+ m/z=360 (M+H)⁺.

Intermediate 5BB3-(5-Cyclobutyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid

A solution of Intermediate 4BB (390 mg, 94% purity, 1.02 mmol) in MeOHand an aqueous NaOH-solution (1.5 ml, 2.0 M, 3.1 mmol) was stirred at RTuntil complete conversion. Water was added and the pH-value adjusted topH: 2. The aqueous phase was extracted with EE, the combined organiclayers dried with Na₂SO₄, filtered and evaporated to dryness underreduced pressure to give 334 mg (95%) of the title compound which wasused without further purification.

LCMS, method 1, rt: 1.23 min, MS ES+ m/z=346 (M+H)⁺.

Intermediate 4BC Methyl3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

A mixture of Intermediate 8 (870 mg, 2.50 mmol),2-bromo-5-(propan-2-yl)-1,3-thiazole (669 mg, 3.25 mmol),[1,1,-Bis-(diphenylphosphino)-ferrocer]-palladium(II) dichloride (306mg, 375 μmol) and K₂CO₃ (6.0 ml, 1.0 M, 6.0 mmol) in THF (41 mL) wasstirred under reflux until complete conversion and evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography (silica gel, hexane/EE/MeOH gradient) to give 451 mg (52%yield) of the title compound.

LCMS, method 1, rt: 1.41 min, MS ES+: MS ES+ m/z=348 (M+H)⁺.

Intermediate 5BC3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid

A solution of Intermediate 4BC (390 mg, 94% purity, 1.06 mmol) in MeOHand an aqueous NaOH-solution (1.6 ml, 2.0 M, 3.2 mmol) was stirred at RTuntil complete conversion. Water was added and the pH-value adjusted topH: 2. The aqueous phase was extracted with EE, the combined organiclayers dried with Na₂SO₄, filtered and evaporated to dryness underreduced pressure to give 400 mg of the title compound which was usedwithout further purification.

LCMS, method 1, rt: 1.17 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 6AZ (3R)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate

A mixture of (3R)-tetrahydrofuran-3-ol (18 g, 204 mmol), TEA (42.7 ml,306 mmol), trimethylamine hydrochloride (1.95 g, 20.4 mmol) in DCM (626mL) was stirred at RT for 20 min. 4-methylbenzenesulfonyl chloride (42.8g, 225 mmol) was added and the reaction mixture stirred at RT untilcomplete conversion. To the reaction mixture N,N-Dimethylethylenediamine(26.4 ml, 245 mmol) was added and stirred for 30 min to consume theunreacted 4-methylbenzenesulfonyl chloride. Water was added and themixture was extracted with DCM (3×). The combined organic layers wereevaporated to dryness under reduced pressure and the residue waspurified by column chromatography (silica gel, hexane/EE/DCM/MeOHgradient) to give 41.0 g (83% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.79-1.95 (m, 1 H) 2.08 (dtd, 1 H)2.43 (s, 3 H) 3.57-3.81 (m, 4 H) 5.12 (ddt, 1 H) 7.49 (d, 2 H) 7.81 (d,2 H).

Intermediate 95 Methyl 3-bromo-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

A mixture of Intermediate 1 (3.00 g, 13.0 mmol), Intermediate 6AZ (4.72g, 19.5 mmol) and Cs₂CO₃ (6.35 g, 19.5 mmol) in DMF 25 ml was stirred at80° C. until complete conversion. The reaction mixture was cooled to RTand the solid was filtered through Celite® and washed with DMF. Thefiltrate was evaporated and the residue purified by columnchromatography (silica gel, hexane/EE gradient) to give 2.63 g (67%yield) of the title compound.

LCMS, method 1, rt: 1.17 min, MS ES+ m/z=301 (M+H)⁺.

Intermediate 94 Methyl3-[(3S)-tetrahydrofuran-3-yloxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of Intermediate 95 (2.63 g, 8.73 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (5.54 g, 21.8mmol), potassium acetate (3.00 g, 30.6 mmol) and[1,1,-Bis-(diphenylphosphino)-ferrocer]-palladium(II) dichloride (638mg, 873 μmol) in 1,4-dioxane (50 mL) was stirred at 90° C. untilcomplete conversion. The mixture was filtered through Celite® and thefiltrate evaporated to dryness under reduced pressure. The residue waspurified by column chromatography (silica gel, hexane/EE/MeOH gradient)to give 4.36 g of the title compound.

LCMS, method 1, rt: 1.31 min, MS ES+ m/z=349 (M+H)⁺.

Intermediate 4BD Methyl3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

A mixture of Intermediate 94 (1.00 g, 2.87 mmol),2-bromo-5-ethyl-1,3-thiazole (662 mg, 3.45 mmol),[1,1,-Bis-(diphenylphosphino)-ferrocer]-palladium(II) dichloride (352mg, 431 μmol) and K₂CO₃ (6.9 ml, 1.0 M, 6.9 mmol) in THF (47 mL) wasstirred under reflux until complete conversion and evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography (silica gel, hexane/EE gradient) to give 327 mg (34%yield) of the title compound.

LCMS, method 1, rt: 1.33 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 5BD3-(5-Ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid

A solution of Intermediate 4BD (327 mg, 94% purity, 922 μmol) in MeOH(8.5 mL), THF (8.5 mL) and an aqueous NaOH-solution (920 μl, 2.0 M, 1.8mmol) was stirred at RT until complete conversion. Water was added andthe pH-value adjusted to pH: 2. The aqueous phase was extracted with EE,the combined organic layers dried with Na₂SO₄, filtered and evaporatedto dryness under reduced pressure to give 299 mg of the title compoundwhich was used without further purification.

LCMS, method 1, rt: 1.10 min, MS ES+ m/z=320 (M+H)⁺.

Intermediate 4BE Methyl3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 94 (1.00 g, 2.87 mmol) with2-chloro-5-cyclobutyl-1,3-thiazole (648 mg, 3.73 mmol) gave 410 mg (39%yield) of the title compound.

LCMS, method 1, rt: 1.46 min, MS ES+ m/z=360 (M+H)⁺.

Intermediate 5BE3-(5-Cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BE (410 mg, 94% purity, 1.07 mmol) gave413 mg of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.22 min, MS ES+ m/z=346 (M+H)⁺.

Intermediate 4BF Methyl3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 94 (1.00 g, 2.87 mmol) with2-bromo-5-(propan-2-yl)-1,3-thiazole (710 mg, 3.45 mmol) gave 374 mg(37% yield) of the title compound.

LCMS, method 1, rt: 1.41 min, MS ES+ m/z=348 (M+H)⁺.

Intermediate 5BF3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BF (374 mg, 94% purity, 1.01 mmol) gave333 mg (99% yield) of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.17 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 4BG Methyl3-(5-chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 94 (500 mg, 1.44 mmol) with2,5-dichloro-1,3-thiazole (288 mg, 1.87 mmol) gave 347 mg (71% yield) ofthe title compound.

LCMS, method 1, rt: 1.36 min, MS ES+ m/z=340 (M+H)⁺.

Intermediate 5BG3-(5-Chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BG (347 mg, 1.02 mmol) gave 300 mg (90%yield) of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.12 min, MS ES+ m/z=326 (M+H)⁺.

Intermediate 4BH Methyl3-(5-chloro-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

In analogy to the conversion of Intermediate 8 to Intermediate 4BA,reaction of

Intermediate 8 (500 mg, 1.44 mmol) with 2,5-dichloro-1,3-thiazole (288mg, 1.87 mmol) gave 249 mg (51% yield) of the title compound.

LCMS, method 1, rt: 1.36 min, MS ES+ m/z=340 (M+H)⁺.

Intermediate 5BH3-(5-Chloro-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid

In analogy to the conversion of Intermediate 4BA to Intermediate 5BA,saponification of Intermediate 4BH (239 mg, 703 μmol) gave 282 mg of thetitle compound which was used without further purification.

LCMS, method 1, rt: 1.11 min, MS ES+ m/z=326 (M+H)⁺.

Intermediate 4BI Methyl3-(5-chloro-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 14W (500 mg, 1.38 mmol) with2,5-dichloro-1,3-thiazole (255 mg, 1.66 mmol) gave 380 mg (78% yield) ofthe title compound.

LCMS, method 1, rt: 1.42 min, MS ES+ m/z=354 (M+H)⁺.

Intermediate 5BI3-(5-Chloro-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BI (300 mg, 848 μmol) gave 353 mg of thetitle compound which was used without further purification.

LCMS, method 1, rt: 1.17 min, MS ES+ m/z=340 (M+H)⁺.

Intermediate 6BA (3R)-Tetrahydrofuran-3-ylmethyl4-methylbenzenesulfonate

In analogy to the synthesis of Intermediate 6AZ, reaction of(3S)-tetrahydrofuran-3-ylmethanol (5.4 g, 52.87 mmol) with4-methylbenzenesulfonyl chloride (11.09 g, 58.16 mmol) gave 12.26 g (90%yield) of the title compound.

LCMS, method 1, rt: 1.02 min, MS ES+ m/z=257 (M+H)⁺.

Intermediate 97 Methyl3-bromo-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoate

In analogy to the reaction of Intermediates 1 and 6AZ to Intermediate95, reaction of Intermediate 1 (2.25 g, 9.75 mmol) with Intermediate 6BA(3.0 g, 11.7 mmol) gave 3.44 g of the title compound.

LCMS, method 1, rt: 1.25 min, MS ES+ m/z=317 (M+H)⁺.

Intermediate 96 Methyl3-[(3R)-tetrahydrofuran-3-ylmethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

In analogy to the conversion of Intermediate 95 to Intermediate 94,reaction of Intermediate 97 (4.11 g, 13.0 mmol) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (8.28 g, 32.6mmol) gave 5.16 g of the title compound.

LCMS, method 1, rt: 1.43 min, MS ES+ m/z=363 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.26-1.33 (m, 12 H) 1.61-1.74 (m, 1 H)1.92-2.11 (m, 1 H) 2.56-2.75 (m, 1 H) 3.53 (dd, 1 H) 3.65 (d, 1 H)3.71-3.82 (m, 2 H) 3.85 (s, 3H) 3.96 (d, 1H) 4.00 (d, 1 H) 7.38 (dd, 1H) 7.54 (dd, 1 H) 7.84 (d, 1 H).

Intermediate 4BJ Methyl3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 96 (1.00 g, 2.76 mmol) with2-bromo-5-ethyl-1,3-thiazole (583 mg, 3.04 mmol) gave 493 mg (51% yield)of the title compound.

LCMS, method 1, rt: 1.38 min, MS ES+ m/z=348 (M+H)⁺.

Intermediate 5BJ3-(5-Ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BJ (490 mg, 94% purity, 1.33 mmol) gave448 mg of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.15 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 4BK Methyl3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 96 (1.00 g, 2.76 mmol) with2-bromo-5-(propan-2-yl)-1,3-thiazole (626 mg, 3.04 mmol) gave 445 mg(45% yield) of the title compound.

LCMS, method 1, rt: 1.46 min, MS ES+ m/z=362 (M+H)⁺.

Intermediate 5BK3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxyl]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BK (450 mg, 94% purity, 1.17 mmol) gave400 mg (98% yield) of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.23 min, MS ES+ m/z=348 (M+H)⁺.

Intermediate 6BB (2R)-Tetrahydrofuran-2-ylmethyl4-methylbenzenesulfonate

In analogy to the synthesis of Intermediate 6AZ, reaction of(2R)-tetrahydrofuran-2-ylmethanol (4.00 g, 39.2 mmol) with4-methylbenzenesulfonyl chloride (8.21 g, 43.1 mmol) gave 10.1 g of thetitle compound.

LCMS, method 1, rt: 1.05 min, MS ES+ m/z=257 (M+H)⁺.

Intermediate 99 Methyl3-bromo-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate

In analogy to the reaction of Intermediates 1 and 6AZ to Intermediate95, reaction of Intermediate 1 (4.94 g, 21.4 mmol) with Intermediate 6BB(6.58 g, 25.7 mmol) gave 6.26 g (93% yield) of the title compound.

Intermediate 98 Methyl3-[(2R)-tetrahydrofuran-2-ylmethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

In analogy to the conversion of Intermediate 95 to Intermediate 94,reaction of Intermediate 99 (6.26 g, 19.9 mmol) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (12.6 g, 49.7mmol) gave 6.26 g (87% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.23-1.39 (m, 12 H) 1.66-1.77 (m, 1 H)1.78-1.94 (m, 2 H) 1.94-2.04 (m, 1 H) 3.62-3.72 (m, 1 H) 3.73-3.82 (m, 1H) 3.86 (s, 3 H) 3.94-4.08 (m, 2 H) 4.11-4.22 (m, 1 H) 7.39 (dd, 1 H)7.55 (dd, 1 H) 7.81-7.89 (m, 1 H).

Intermediate 4BL Methyl3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 98 (1.00 g, 2.76 mmol) with2-bromo-5-ethyl-1,3-thiazole (583 mg, 3.04 mmol) gave 182 mg (19% yield)of the title compound.

LCMS, method 1, rt: 1.39 min, MS ES+ m/z=348 (M+H)⁺.

Intermediate 5BL3-(5-Ethyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BL (188 mg, 94% purity, 509 μmol) gave185 mg of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.17 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 4BM Methyl3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 98 (1.00 g, 2.76 mmol) with2-chloro-5-cyclobutyl-1,3-thiazole (527 mg, 3.04 mmol) gave 329 mg (32%yield) of the title compound.

LCMS, method 1, rt: 1.52 min, MS ES+ m/z=374 (M+H)⁺.

Intermediate 5BM3-(5-Cyclobutyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BM (329 mg, 94% purity, 828 μmol) gave316 mg of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.30 min, MS ES+ m/z=360 (M+H)⁺.

Intermediate 4BN Methyl3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 98 (1.00 g, 2.76 mmol) with2-bromo-5-(propan-2-yl)-1,3-thiazole (626 mg, 3.04 mmol) gave 386 mg(39% yield) of the title compound.

LCMS, method 1, rt: 1.47 min, MS ES+ m/z=362 (M+H)⁺.

Intermediate 5BN3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BN (386 mg, 94% purity, 1.00 mmol) gave401 mg of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.26 min, MS ES+ m/z=348 (M+H)⁺.

Intermediate 101 Methyl3-bromo-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

In analogy to the reaction of Intermediates 1 and 6AZ to Intermediate95, reaction of Intermediate 1 (4.85 g, 21.0 mmol) with Intermediate 17A(6.45 g, 25.2 mmol) gave 7.47 g of the title compound.

LCMS, method 1, rt: 1.25 min, MS ES+ m/z=315 (M+H)⁺.

Intermediate 100 Methyl3-[(3S)-tetrahydrofuran-3-ylmethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

In analogy to the conversion of Intermediate 95 to Intermediate 94,reaction of Intermediate 101 (7.47 g, 23.7 mmol) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (15.0 g, 59.3mmol) gave 9.27 g of the title compound.

LCMS, method 1, rt: 1.36 min, MS ES+ m/z=363 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.27-1.33 (m, 12 H) 1.63-1.78 (m, 1 H)1.94-2.07 (m, 1 H) 2.56-2.72 (m, 1 H) 3.54 (dd, 1 H) 3.66 (d, 1 H)3.73-3.83 (m, 2 H) 3.86 (s, 3 H) 3.99 (dd, 2 H) 7.39 (dd, 1 H) 7.55 (dd,1 H) 7.81-7.89 (m, 1 H).

Intermediate 4BO Methyl3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 100 (1.00 g, 2.76 mmol) with2-bromo-5-ethyl-1,3-thiazole (583 mg, 3.04 mmol) gave 538 mg (56% yield)of the title compound.

LCMS, method 1, rt: 1.38 min, MS ES+ m/z=348 (M+H)⁺.

Intermediate 5BO3-(5-Ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BO (538 mg, 94% purity, 1.46 mmol) gave525 mg of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.15 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 4BP Methyl3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 100 (1.00 g, 2.76 mmol) with2-bromo-5-(propan-2-yl)-1,3-thiazole (626 mg, 3.04 mmol) gave 570 mg(57% yield) of the title compound.

LCMS, method 1, rt: 1.46 min, MS ES+ m/z=362 (M+H)⁺.

Intermediate 5BP3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BP (570 mg, 94% purity, 1.48 mmol) gave534 mg of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.22 min, MS ES+ m/z=348 (M+H)⁺.

Intermediate 46Q Methyl3-(5-chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 100 (100 mg, 276 μmol) with2,5-dichloro-1,3-thiazole (51.0 mg, 331 μmol) gave 77.8 mg (80% yield)of the title compound.

LCMS, method 1, rt: 1.42 min, MS ES+ m/z=354 (M+H)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 1.71 (d, 1 H) 1.98-2.11 (m, 1 H)2.61-2.75 (m, 1 H) 3.57 (dd, 1 H) 3.67 (td, 1 H) 3.73-3.85 (m, 2 H) 3.89(s, 3 H) 3.98-4.05 (m, 1 H) 4.06-4.16 (m, 1 H) 7.55 (dd, 1 H) 7.64 (dd,1 H) 7.96-8.06 (m, 2 H).

Intermediate 5BQ3-(5-Chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BQ (347 mg, 981 μmol) gave 329 mg (99%yield) of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.18 min, MS ES+ m/z=340 (M+H)⁺.

Intermediate 6BC (2S)-Tetrahydrofuran-2-ylmethyl4-methylbenzenesulfonate

In analogy to the synthesis of Intermediate 6AZ, reaction of(2S)-tetrahydrofuran-2-ylmethanol (3.00 g, 29.4 mmol) with4-methylbenzenesulfonyl chloride (6.16 g, 32.3 mmol) gave 6.22 g (83%yield) of the title compound.

LCMS, method 1, rt: 1.06 min, MS ES+ m/z=257 (M+H)⁺.

Intermediate 103 Methyl3-bromo-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate

In analogy to the reaction of Intermediates 1 and 6AZ to Intermediate95, reaction of Intermediate 1 (4.94 g, 21.4 mmol) with Intermediate 6BC(6.58 g, 25.7 mmol) gave 4.08 g (61% yield) of the title compound.

LCMS, method 1, rt: 1.26 min, MS ES+ m/z=315 (M+H)⁺.

Intermediate 102 Methyl3-[(2S)-tetrahydrofuran-2-ylmethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

In analogy to the conversion of Intermediate 95 to Intermediate 94,reaction of

Intermediate 103 (4.08 g, 12.9 mmol) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (8.22 g, 32.4mmol) gave 6.62 g (80% yield) of the title compound.

LCMS, method 1, rt: 1.40 min, MS ES− m/z=641 (M−H)⁻.

Intermediate 4BR Methyl3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 102 (1.00 g, 2.76 mmol) with2-bromo-5-ethyl-1,3-thiazole (583 mg, 3.04 mmol) gave 480 mg (50% yield)of the title compound.

LCMS, method 1, rt: 1.40 min, MS ES+ m/z=348 (M+H)⁺.

Intermediate 5BR3-(5-Ethyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BR (480 mg, 94% purity, 1.30 mmol) gave552 mg of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.19 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 4BS Methyl3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of Intermediate 102 (1.00 g, 2.76 mmol) with2-chloro-5-cyclobutyl-1,3-thiazole (527 mg, 3.04 mmol) gave 590 mg (58%yield) of the title compound.

LCMS, method 1, rt: 1.52 min, MS ES+ m/z=374 (M+H)⁺.

Intermediate 5BS3-(5-Cyclobutyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BS (594 mg, 94% purity, 1.50 mmol) gave634 mg of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.31 min, MS ES+ m/z=360 (M+H)⁺.

Intermediate 4BT Methyl3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate

In analogy to the conversion of Intermediate 94 to Intermediate 4BD,reaction of

Intermediate 102 (1.00 g, 2.76 mmol) with2-bromo-5-(propan-2-yl)-1,3-thiazole (626 mg, 3.04 mmol) gave 485 mg(49% yield) of the title compound.

LCMS, method 1, rt: 1.47 min, MS ES+ m/z=362 (M+H)⁺.

Intermediate 5BT3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BT (490 mg, 94% purity, 1.27 mmol) gave444 mg (100% yield) of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.25 min, MS ES+ m/z=348 (M+H)⁺.

Intermediate 104 1-(2,2,2-Trifluoroethyl)piperidin-4-ol

A mixture of 1-(2,2,2-trifluoroethyl)piperidin-4-one (2.40 g, 13.2mmol), NaBH₄ (1.50 g, 39.7 mmol) in MeOH was stirred at rt for 16 hours.A saturated aqueous NaHCO₃-solution was added and the aqueous layerextracted with DCM (3×). The combined organic layers were reduced todryness under reduced pressure to give 2.14 g (88% yield) which was usedwithout further purification.

Intermediate 6BD 1-(2,2,2-Trifluoroethyl)piperidin-4-yl4-methylbenzenesulfonate

In analogy to the synthesis of Intermediate 6AZ, reaction ofIntermediate 104 (2.14 g, 11.7 mmol) with 4-methylbenzenesulfonylchloride (2.45 g, 12.9 mmol) gave 3.70 g (94% yield) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.59 (m, 2 H) 1.65-1.79 (m, 2 H) 2.42(s, 3 H) 2.70 (m, 2 H) 3.14 (q, J=10.31 Hz, 2 H) 4.52 (dt, 1 H) 7.47 (d,2 H) 7.75-7.86 (m, 2 H).

Intermediate 4BU Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzoate

In analogy to the reaction of Intermediates 3A with 6AY to Intermediate4AZ, reaction of Intermediate 3 (1.89 g, 7.59 mmol) with Intermediate6BD (3.7 g, 90% purity, 9.87 mmol) gave 2.0 g (64% yield) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.69 (d, 2 H) 1.93 (d, 2 H) 2.58-2.69(m, 2 H) 2.78-2.92 (m, 2 H) 3.13-3.27 (m, 2 H) 3.89 (s, 3 H) 4.55-4.69(m, 1 H) 7.51 (dd, 1 H) 7.61-7.69 (m, 2 H) 7.97 (t, 1 H).

Intermediate 5BU3-(5-Methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BU (2.0 g, 4.83 mmol) gave 1.9 g (98%yield) of the title compound which was used without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.58-1.77 (m, 2 H) 1.95 (dd, 2 H)2.57-2.69 (m, 2 H) 2.76-2.94 (m, 2 H) 3.20 (q, 2 H) 4.46-4.67 (m, 1 H)7.50 (dd, 1 H) 7.53-7.69 (m, 2 H) 7.95 (t, 1 H).

Intermediate 105 1-(2,2-Difluoroethyl)piperidin-4-ol

In analogy to the synthesis of Intermediate 104, reduction of1-(2,2-difluoroethyl)piperidin-4-one (2.70 g, 16.5 mmol) gave 2.20 g(80% yield) of the title compound which was used without furtherpurification.

Intermediate 6BE 1-(2,2-Difluoroethyl)piperidin-4-yl4-methylbenzenesulfonate

In analogy to the synthesis of Intermediate 6AZ, reaction ofIntermediate 105 (2.20 g, 13.3 mmol) with 4-methylbenzenesulfonylchloride (2.79 g, 14.7 mmol) gave 4.80 g of the title compound.

LCMS, method 1, rt: 0.86 min, MS ES+ m/z=320 (M+H)⁺.

Intermediate 4BV Methyl3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

In analogy to the reaction of Intermediates 3A with 6AY to Intermediate4AZ, reaction of Intermediate 3 (2.25 g, 9.02 mmol) with Intermediate6BE (4.80 g, 90% purity, 13.5 mmol) gave 2.1 g (59% yield) of the titlecompound.

LCMS, method 1, rt: 0.94 min, MS ES+ m/z=397 (M+H)⁺.

Intermediate 5BV3-{[1-(2,2-Difluoroethyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BV (2.10 g, 5.30 mmol) gave 600 mg (30%yield) of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 0.76 and 0.83 min, MS ES+ m/z=383 (M+H)⁺.

Intermediate 6BF (3-Methyloxetan-3-yl)methyl 4-methylbenzenesulfonate

In analogy to the synthesis of Intermediate 6AZ, reaction of(3-methyloxetan-3-yl)methanol (630 mg, 6.17 mmol) with4-methylbenzenesulfonyl chloride (1.29 g, 6.79 mmol) gave 1.20 g (76%yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13-1.23 (m, 3 H) 2.43 (s, 3 H) 4.11(s, 2 H) 4.15-4.20 (m, 2 H) 4.22-4.28 (m, 2 H) 7.50 (d, 2 H) 7.77-7.86(m, 2 H).

Intermediate 4BW Methyl3-[(3-methyloxetan-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

In analogy to the reaction of Intermediates 3A with 6AY to Intermediate4AZ, reaction of Intermediate 3 (200 mg, 802 μmol) with Intermediate 6BF(308 mg, 1.20 mmol) gave 80.0 mg (30% yield) of the title compound.

LCMS, method 1, rt: 1.24 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 5BW3-[(3-Methyloxetan-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BW (80.0 mg, 240 μmol) gave 75.0 mg (98%yield) of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.03 min, MS ES+ m/z=320 (M+H)⁺.

Intermediate 6BG (2-Methyltetrahydrofuran-2-yl)methyl4-methylbenzenesulfonate, mixture of two enantiomers

In analogy to the synthesis of Intermediate 6AZ, reaction of racemic(2-methyltetrahydrofuran-2-yl)methanol (944 mg, 8.13 mmol) with4-methylbenzenesulfonyl chloride (1.70 g, 8.94 mmol) gave 1.68 g (76%yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 0.99-1.12 (s, 3 H) 1.47-1.65 (m, 1H)1.66-1.89 (m, 3 H) 2.37-2.47 (s, 3 H) 3.49-3.63 (m, 1 H) 3.63-3.74 (m, 1H) 3.78-3.92 (m, 2 H) 7.49 (d, 2 H) 7.72-7.96 (d, 2 H).

Intermediate 5BX3-[(2-Methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, mixture of two enantiomers

A mixture of Intermediate 3 (400 mg, 1.60 mmol), Intermediate 6BG (650mg, 2.40 mmol) and Cs₂CO₃ (783 mg, 2.40 mmol) in DMF (12 mL) was stirredat 90° C. for 3 days. The mixture was filtrated and the filtrateevaporated to dryness under reduced pressure to give 2.34 of the titlecompound which was used without further purification.

LCMS, method 1, rt: 1.18 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 6BH (3-Methyltetrahydrofuran-3-yl]methyl4-methylbenzenesulfonate, mixture of two enantiomers

In analogy to the synthesis of Intermediate 6AZ, reaction of racemic(3-methyltetrahydrofuran-3-yl)methanol (1.00 g, 8.61 mmol) with4-methylbenzenesulfonyl chloride (1.81 g, 9.47 mmol) gave 2.00 g (82%yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 0.93-1.05 (m, 3 H) 1.54 (ddd, 1 H)1.69 (ddd, 1 H) 2.37-2.47 (m, 3 H) 3.22 (d1 H) 3.45 (d, 1 H) 3.59-3.73(m, 2 H) 3.81-3.92 (m, 2 H) 7.50 (d, 2 H) 7.80 (d, 2 H).

Intermediate 4BY Methyl3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate,mixture of two enantiomers

In analogy to the reaction of Intermediates 3A with 6AY to Intermediate4AZ, reaction of Intermediate 3 (1.11 g, 4.44 mmol) with Intermediate6BH (2.00 g, 90% purity, 6.66 mmol) gave 1.10 g (75% purity, 53% yield)of the title compound.

LCMS, method 1, rt: 1.37 min, MS ES+ m/z=348 (M+H)⁺.

Intermediate 5BY3-[(3-Methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, mixture of two enantiomers

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BY (1.10 g, 3.17 mmol) gave 700 mg (63%yield) of the title compound which was used without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.21 (s, 3 H) 1.67 (ddd, 1 H)1.86-2.01 (m, 1 H) 3.39 (d, 1 H) 3.71 (d, 1 H) 3.75-3.88 (m, 2 H)3.90-4.03 (m, 2 H) 7.53 (dd, 1 H) 7.56-7.67 (m, 2 H) 7.98 (t, 1 H).

Intermediate 4BI 1-Methyl-6-oxopiperidin-3-yl 4-methylbenzenesulfonate,Mixture of Two Enantiomers

In analogy to the synthesis of Intermediate 6AZ, reaction of racemic5-hydroxy-1-methylpiperidin-2-one (800 mg, 6.19 mmol) with4-methylbenzenesulfonyl chloride (1.33 g, 6.81 mmol) gave 1.33 g (76%yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.74-1.87 (m, 1 H) 1.87-2.01 (m, 1 H)2.15-2.25 (m, 2 H) 2.43 (s, 3 H) 2.71 (s, 3 H) 3.19-3.28 (m, 1 H) 3.53(dd, 1 H) 4.88-5.02 (m, 1 H) 7.49 (d, 2 H) 7.79-7.91 (m, 2 H).

Intermediate 4BZ Methyl3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate,mixture of two enantiomers

In analogy to the reaction of Intermediates 3A with 6AY to Intermediate4AZ, reaction of Intermediate 3 (702 mg, 2.82 mmol) with Intermediate4BI (1.33 g, 90% purity, 4.22 mmol) gave 350 mg (34% yield) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 2.06 (br. s., 2 H) 2.20-2.30 (m, 1 H)2.31-2.42 (m, 1 H) 2.81 (s, 3 H) 3.41-3.46 (m, 1 H) 3.65 (m, 1 H) 3.89(s, 3 H) 4.99-5.13 (m, 1 H) 7.57 (dd, 1 H) 7.63-7.74 (m, 2 H) 8.02 (t, 1H).

Intermediate 5BZ3-[(1-Methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, mixture of two enantiomers

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4BZ (350 mg, 971 μmol) gave 330 mg (98%yield) of the title compound which was used without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 2.01-2.10 (m, 2 H) 2.21-2.31 (m, 1 H)2.31-2.42 (m, 1 H) 2.79-2.84 (m, 3 H) 3.39-3.45 (m, 2 H) 3.66 (dd, 1 H)5.05 (m, 1 H) 7.55 (dd, 1 H) 7.62-7.71 (m, 2 H) 8.00 (t, 1 H).

Intermediate 4CA Methyl3-[(2-hydroxycyclopentyl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate,mixture of two trans stereoisomers

A mixture of Intermediate 3 (360 mg, 1.44 mmol),6-oxabicyclo[3.1.0]hexane (182 mg, 2.17 mmol), KOtBu (16.2 mg, 144 μmol)in DMF (11 mL) was stirred at 130° C. for 6 hours. To this mixture wasadded water and DCM, and the phases were separated. The organic layerwas extracted with DCM (3×). The combined organic layers were evaporatedto dryness and the residue was purified by column chromatography to give800 mg of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 1.21 min, MS ES+ m/z=334 (M+H)⁺.

Intermediate 5CA3-[(2-Hydroxycyclopentyl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid,mixture of two trans stereoisomers

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4CA (500 mg, 1.50 mmol) gave 380 mg (79%yield) of the title compound which was used without furtherpurification.

Intermediate 5CB3-[(3-Hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid,mixture of two trans stereoisomers

Intermediate 3 (600 mg, 2.4 mmol) and cis-2,3-epoxybutane (840 μl, 9.6mmol) in THF (18.0 mL) were treated with NaOH (14.4 ml, 1.0 M, 14.4mmol) and heated under reflux for 72 hours. The pH-value was adjusted topH: 5, the reaction mixture extracted with ethyl acetate, the combinedorganic layers dried with

Na₂SO₄, filtered and evaporated to dryness under reduced pressure togive 1.30 g of the title compound which was used without furtherpurification.

LCMS, method 1, rt: 0.97 min, MS ES+ m/z=308 (M+H)⁺.

Intermediate 4CC Methyl3-(2-hydroxy-2-methylpropoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of Intermediate 3 (221 mg, 887 μmol), 2,2-dimethyloxirane (320mg, 4.43 mmol) and K₂CO₃ (245 mg, 1.77 mmol) in DMSO (17 mL) was stirredfor 3 hours at 130° C. The mixture was evaporated to dryness underreduced pressure and purified by column chromatography (silica gel) togive 230 mg (81% yield) of the title compound.

Intermediate 5CC3-(2-Hydroxy-2-methylpropoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

In analogy to the conversion of Intermediate 4BD to Intermediate 5BD,saponification of Intermediate 4CC (230 mg, 716 μmol) gave 180 mg (82%yield) of the title compound which was used without furtherpurification.

Intermediate 106 Tert-butyl9-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate,Mixture of Two Stereoisomers (Syn/Anti)

To a solution of tert-butyl9-hydroxy-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate (mixture of twostereoisomers (syn/anti), 900 mg, 3.70 mmol) in DMF (12 mL) was addedNaH (148 mg, 60% purity, 3.70 mmol) and the mixture was stirred at RTfor 1 hour. Intermediate 26 was added (621 mg, 2.85 mmol) and theresulting mixture stirred for 17 hours at RT. Water was careful added,the mixture stirred for 30 min and extracted with EE. The combinedorganic layers were washed with water and saturated aqueousNaCl-solution, dried with Na₂SO₄, filteres and evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography to give 665 mg (53% yield) of the title compound.

LCMS, method 1, rt: 1.40 min, MS ES+ m/z=442 (M+H)⁺.

Intermediate 1073-{[7-(Tert-butoxycarbonyl)-3-oxa-7-azabicyclo[3.3.1]non-9-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, Mixture of Two Stereoisomers (Syn/Anti)

To a solution of Intermediate 106 (670 mg, 1.52 mmol) in DMSO (5 mL) wasadded sodium hydroxide (7.6 ml, 2.0 M, 15 mmol) and the mixture stirredat 110° C. for 3 hours. The mixture was acidified with 2 M aqueousHCl-solution and the pH-value adjusted to pH: 5. The solution wasextracted with EE, the combined organic layers dried with Na₂SO₄,filtered and evaporated to dryness under reduced pressure to give 808 mgof the title compound which was used without further purification.

LCMS, method 1, rt: 1.23 min, MS ES+ m/z=461 (M+H)⁺.

Intermediate 108 Tert-butyl9-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate,Mixture of Two Stereoisomers (Syn/Anti)

A mixture of Intermediate 107 (1.61 g, 3.50 mmol), Intermediate VI (1:1)(1.11 g, 4.89 mmol), HATU (3.19 g, 8.39 mmol) and DIPEA (3.0 ml, 17mmol) in DMF (160 mL) was stirred at ambient temperature for 12 hours.The reaction mixture was evaporated to dryness under reduced pressureand the residue purified by column chromatography (silica gel) to give1.35 g (58% yield) of the title compound.

LCMS, method 1, rt: 1.38 min, MS ES+ m/z=634 (M+H)⁺.

Intermediate 1093-(5-Methyl-1,3-thiazol-2-yl)-5-(3-oxa-7-azabicyclo[3.3.1]non-9-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,Mixture of Two Stereoisomers (Syn/Anti)

A mixture of Intermediate 108 (1.32 g, 2.08 mmol) and TFA (3.2 ml, 42mmol) in DCM (110 mL) was stirred at RT for 17 hours. The mixture wasevaporated to dryness under reduced pressure and purified by columnchromatography to give (818 mg, 73% yield) of the title compound.

LCMS, method 1, rt: 0.90 min, MS ES+ m/z=534 (M+H)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 1.62 (d, 3 H) 2.11-2.19 (m, 1 H)2.20-2.30 (m, 1 H) 3.38-3.49 (m, 2 H) 3.54-3.67 (m, 1 H) 3.83-3.94 (m, 2H) 4.05-4.20 (m, 2 H) 4.96-5.13 (m, 1 H) 5.18-5.37 (m, 1 H) 7.66 (m, 3H) 7.98 (s, 1 H) 9.12 (d, 2 H) 9.17-9.28 (m, 1 H).

Intermediate 6CD tert-butyl(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl) morpholine-4-carboxylate

To tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate (5 g, 23mmol), TEA (4.8 mL, 34.5 mmol) and trimethylamine hydrochloride (210 mg,2.2 mmol) in DCM (60 mL) was added 4-methylbenzenesulfonyl chloride (6.6g, 34.5 mmol) and the mixture stirred at RT overnight. The reactionmixture was treated with N,N-dimethylethane-1,2-diamine (1.5 mL, 13.8mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Thereaction mixture was washed with 1 M HCl and water. The organic fractiondried (sodium sulfate), filtered and concentrated under reduced pressureto give 10.1 g (99% yield) of the title compound as yellow oil, whichsolidified upon standing.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 1.38 (s, 9H), 2.43 (s, 3H), 2.55-2.71(m, 1H), 2.71-2.89 (m, 1H), 3.24-3.41 (m, 1H), 3.52 (m, 1H), 3.59-3.84(m, 3H), 3.92-4.14 (m, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.3 Hz,2H).

Intermediate 110 (2R)-2-[(Benzyloxy)methyl]morpholine

To a stirred mixture of (2R)-2-[(benzyloxy)methyl]oxirane (27.7 g, 0.17mol) and NaOH (54.0 g, 1.3 mol) in water (130 mL) and MeOH (50 mL) wasadded 2-aminoethyl hydrogen sulfate (100 g, 0.7 mol) portionwise. Afteraddition was complete, the reaction mixture was stirred at 40° C. for 2h. On cooling, the mixture was treated with a further portion of NaOH(40.5 g, 1.0 mol), followed by toluene (200 mL) and stirred at 65° C.overnight. The mixture was cooled, diluted with toluene and water. Thetoluene layer was separated and the aqueous layer extracted with DCM(2×100 mL). The combined organic layers were concentrated to give thetitle compound, which was used in the next step without purification.

Intermediate 111 Tert-butyl(2R)-2-[(benzyloxy)methyl]morpholine-4-carboxylate

A solution of Intermediate 110 in acetone (400 mL) and water (120 mL)was cooled to 0° C. and potassium carbonate (70 g, 0.5 mol) was addedfollowed by di-tert-butyl dicarbonate (44 g, 0.2 mol). The reactionmixture was allowed to warm to ambient temperature and was stirred for18 h. Acetone was removed under reduced pressure and the aqueoussolution extracted twice with EtOAc. The combined organics were dried(MgSO₄), filtered and concentrated under reduced pressure. The crudematerial was purified by Biotage Isolera™ chromatography (eluting with0-25% EtOAc in heptane on a pre-packed 340 g silica gel column) to give19.8 g (38% yield) of the title compound as pale yellow oil.

¹H NMR (250 MHz, chloroform-d): δ [ppm] 7.39-7.27 (m, 5H), 4.56 (s, 2H),4.03-3.73 (m, 3H), 3.69-3.34 (m, 4H), 3.05-2.86 (m, 1H), 2.84-2.65 (m,1H), 1.46 (s, 9H)

LC-MS (Method A) Rt=1.27 min, MS (ESIpos): m/z=252 (M-tBu)⁺.

Intermediate 112 Tert-butyl(2R)-2-(hydroxymethyl)morpholine-4-carboxylate

Intermediate 111 (19.8 g, 64.4 mmol) was stirred under an atmosphere ofhydrogen in the presence of 10% Pd/C (1.98 g, 1.86 mmol) for 16 h. Thecatalyst was removed by vacuum filtration and the filtrate concentratedat reduced pressure to give 13.98 g (100% yield) of the title compoundas a colourless viscous oil, which crystallised on standing.

¹H NMR (250 MHz, chloroform-d): δ [ppm] 3.98-3.75 (m, 3H), 3.73-3.41 (m,4H), 3.03-2.83 (m, 1H), 2.82-2.65 (m, 1H), 2.12 (t, J=5.9 Hz, 1H), 1.45(s, 9H).

Intermediate 6CE Tert-butyl(2R)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl) morpholine-4-carboxylate

Intermediate 112 (5.96 g, 27.4 mmol), triethylamine (5.74 mL, 41.1 mmol)and trimethylamine hydrochloride (262 mg, 2.74 mmol) were stirred indichloromethane (62 mL) then 4-toluenesulfonyl chloride (7.85 g, 41.1mmol) was added. The reaction was stirred at ambient temperature for 2 hthen treated with N,N-dimethylethane-1,2-diamine (1.81 mL, 16.5 mmol) toconsume unreacted 4-toluenesulfonyl chloride. The reaction mixture waswashed with 1 M HCl (2×100 mL) and water (50 mL). The organic fractionwas dried (sodium sulfate), filtered and concentrated under reducedpressure to give the title compound (11.4 g, 100% yield) as yellow oil.

¹H NMR (500 MHz, chloroform-d): δ [ppm] 7.80 (d, J=8.3 Hz, 2H), 7.35 (d,J=8.0 Hz, 2H), 4.02 (qd, J=10.6, 5.0 Hz, 2H), 3.94-3.74 (m, 3H),3.67-3.55 (m, 1H), 3.46 (td, J=11.6, 2.8 Hz, 1H), 2.98-2.81 (m, 1H),2.75-2.57 (m, 1H), 2.45 (s, 3H), 1.45 (s, 9H).

LC-MS (Method A) Rt=1.28 min, MS (ESIpos): m/z=394 (M+Na)⁺.

Intermediate 4CF Tert-butyl2-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}morpholine-4-carboxylate

Intermediate 3 (300 mg, 1.2 mmol), tert-butyl2-({[(4-methylphenyl)sulfonyl]oxy}methyl)morpholine-4-carboxylate (424.2mg, 1.14 mmol) and cesium carbonate (439.4 mg, 1.32 mmol) were stirredin acetonitrile (5 mL) at 100° C. in a sealed tube for 6 h. The reactionmixture was cooled to RT and filtered through Celite®, washing withEtOAc. The filtrate was concentrated under reduced pressure and purifiedby Biotage Isolera™ chromatography (eluting with 5-70% EtOAc in heptaneon a 25 g pre-packed KP-SiO₂ column) to give 331.1 mg (70% yield) of thetitle compound as a colourless gum.

¹H NMR (250 MHz, chloroform-d): δ [ppm] 8.13 (t, J=1.4 Hz, 1H),7.72-7.68 (m, 1H), 7.61 (dd, J=2.5, 1.4 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H),4.18-4.05 (m, 2H), 3.93 (s, 5H), 3.88-3.76 (m, 2H), 3.67-3.55 (m, 1H),3.07-2.80 (m, 2H), 2.52 (d, J=1.1 Hz, 3H), 1.48 (s, 9H).

Intermediate 4CE Tert-butyl(2R)-2-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}morpholine-4-carboxylate

Intermediate 3 (23.17 g, 70.6 mmol), Intermediate 6CE (28.9 g, 77.7mmol) and cesium carbonate (34.52 g, 105.9 mmol) were combined inacetonitrile (300 mL) and stirred at 100° C. under nitrogen for 2.5 h.The cooled reaction mixture was filtered through Celite®, washing withEtOAc. The filtrate was concentrated under reduced pressure and purifiedby Biotage Isolera™ chromatography (eluting with 0-50% EtOAc in heptaneon a 340 g pre-packed KP-SiO₂ column) to give 27.22 g (69% yield) of thetitle compound as viscous yellow oil.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.13 (t, J=1.4 Hz, 1H), 7.70 (s,1H), 7.61 (dd, J=2.4, 1.3 Hz, 1H), 7.52 (d, J=1.1 Hz, 1H), 4.18-3.78 (m,11H), 3.67-3.54 (m, 1H), 2.95 (m, 2H), 2.52 (d, J=1.0 Hz, 3H), 1.48 (s,9H).

LCMS (Method A) Rt=1.40 min, MS (ESIpos): m/z=449 (M+H)⁺.

In analogy to the procedure described for Intermediate 4CE, thefollowing Intermediates were prepared using the corresponding phenol andtosylate starting materials.

Int. Structure Name Analytical Data 4CD

Tert-butyl (2S)-2-{[3- (methoxy- carbonyl)-5- (5-methyl-1,3- thiazol-2-yl)phenoxy] methyl} morpholine- 4-carboxylate ¹H NMR (250 MHz,chloroform-d): δ [ppm] 8.13 (t, J = 1.4 Hz, 1H), 7.73- 7.66 (m, 1H),7.61 (dd, J = 2.5, 1.4 Hz, 1H), 7.54-7.49 (m, 1H), 4.18-3.99 (m, 3H),3.95-3.75 (m, 6H), 3.67-3.55 (m, 1H), 3.08- 2.80 (m, 2H), 2.52 (d, J =1.1 Hz, 3H), 1.48 (s, 9H). LC-MS (Method A) Rt = 1.36 min, MS (ESIpos)m/z = 449 (M + H)⁺. 4CH

Tert-butyl (2R)-2-{[3-(5- ethyl-1,3- thiazol-2-yl)-5- (methoxy-carbonyl) phenoxy] methyl} morpholine-4- carboxylate ¹H NMR (250 MHz,DMSO-d6): δ [ppm] 1.28 (t, J = 7.2 Hz, 3H), 1.41 (s, 9H), 2.72-3.02 (m,4H), 3.38- 3.56 (m, 1H), 3.61-3.80 (m, 2H), 3.80-4.02 (m, 5H), 4.07-4.29(m, 2H), 7.52 (dd, J = 2.5, 1.4 Hz, 1H), 7.64-7.68 (m, 1H), 7.69 (s,1H), 8.02 (t, J = 1.4 Hz, 1H). LC-MS (Method A) Rt = 1.51 min, MS(ESIpos): m/z = 463 (M + H)⁺. 4CI

Tert-butyl (2S)-2-{[3-(5- ethyl-1,3- thiazol-2-yl)-5- (methoxy-carbonyl) phenoxy] methyl} morpholine-4- carboxylate LC-MS (Method A) Rt= 1.47 min, MS (ESIpos): m/z = 463 (M + H)⁺. 4CJ

Tert-butyl (2S)-2-[[3-(5- chlorothiazol- 2-yl)-5- methoxy- carbonyl-phenoxy] methyl] morpholine- 4-carboxylate ¹H NMR (250 MHz,chloroform-d): δ [ppm] 8.08 (t, J = 1.4 Hz, 1H), 7.71- 7.53 (m, 3H),4.22-3.74 (m, 9H), 3.70-3.53 (m, 1H), 3.13-2.78 (m, 2H), 1.48 (s, 9H).LC-MS (Method A) Rt = 1.50 min, MS (ESIpos): m/z = 491 (M + Na)⁺. 4CK

Tert-butyl (2R)-2-[[3-(5- chlorothiazol- 2-yl)-5- methoxy- carbonyl-phenoxy] methyl] morpholine- 4-carboxylate ¹H NMR (500 MHz,chloroform-d): δ [ppm] 8.08 (s, 1H), 7.71-7.59 (m, 3H), 4.14 (dd, J =9.9, 5.4 Hz, 1H), 4.08 (dd, J = 9.9, 4.5 Hz, 1H), 4.06- 3.99 (m, 1H),3.99-3.96 (m, 1H), 3.94 (s, 3H), 3.92-3.88 (m, 1H), 3.86-3.78 (m, 1H),3.66-3.53 (m, 1H), 3.09-2.96 (m, 1H), 2.97- 2.76 (m, 1H), 1.48 (s, 9H).LC-MS (Method A) Rt = 1.53 min, MS (ESIpos): m/z = 491 (M + H)⁺.

Intermediate 4CG Tert-butyl4-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}piperidine-1-carboxylate

Intermediate 3 (300 mg, 1.20 mmol), 1-Boc-4-bromomethylpiperidine (4.35mg, 1.56 mmol) and cesium carbonate (784 mg, 2.04 mmol) were combined inMeCN (5 mL) and heated to 100° C. for 6 h. After cooling to roomtemperature the reaction mixture was diluted with EtOAc (5 mL), filteredand the filtrate concentrated under reduced pressure. The crude materialwas purified by Biotage Isolera™ chromatography (eluting with 0-40%EtOAc in heptane on a 25 g pre-packed KP-SiO₂ column) to give 272.2 mg(49% yield) of the title compound as colourless gum.

¹H NMR (500 MHz, chloroform-d): δ [ppm] 8.08 (s, 1H), 7.69 (s, 1H), 7.58(s, 1H), 7.53 (s, 1H), 4.24-4.09 (m, 2H), 3.94 (s, 3H), 3.92 (d, J=6.4Hz, 2H), 2.84-2.71 (m, 2H), 2.53 (s, 3H), 2.03-1.95 (m, 1H), 1.84 (d,J=11.5 Hz, 2H), 1.47 (s, 9H), 1.36-1.23 (m, 2H).

LC-MS (Method A) Rt=1.50 min, MS (ESIpos): m/z=447 (M+H)⁺.

Intermediate 4CL Tert-butyl3-fluoro-3-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}azetidine-1-carboxylate

To a stirred 0° C. solution of Intermediate 3 (300 mg, 1.201 mmol),tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (321 mg,1.56 mmol) and triphenylphosphine (1.26 g, 4.81 mmol) in anhydrous THF(3 mL) was added DIAD (472 μL, 2.41 mmol) dropwise. After 10 mins thereaction mixture was warmed to RT and stirred for 16 h. Additional DIAD(200 μL, 1.02 mmol) was added and the reaction stirred at RT for 24 h.Additional DIAD (200 μL, 1.02 mmol) was added and the reaction stirredat RT for 70 h. The reaction mixture was concentrated at reducedpressure and purified by Biotage Isolera™ chromatography (eluting with0-100% gradient EtOAc in heptane on a pre-packed KP-SiO₂ column) to give1.43 g (41% yield) of the title compound as colourless oil. The materialwas used without further purification.

LC-MS (Method A) Rt=1.37 min, MS (ESIpos): m/z=437 (M+H)⁺.

Intermediate 6CV Tert-butyl3-({[(4-methylphenyl)sulfonyl]oxy}methyl)azetidine-1-carboxylate

A mixture of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (600mg, 3.20 mmol), 4-methylbenzenesulfonyl chloride (672 mg, 3.52 mmol),TEA (670 μL, 4.8 mmol), trimethylammonium hydrochloride (30.6 mg, 320μmol) in DCM (3.2 mL) was stirred at RT until complete conversion. Thereaction mixture was evaporated to dryness. Crude material was purifiedby column chromatography (silica gel, hexane/EtOAc gradient) to give 800mg (73% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.34 (s, 9H), 2.43 (s, 3H), 2.73-2.87(m, 1H), 3.46 (br. s., 2H), 3.74-3.91 (m, 2H), 4.16 (d, 2H), 7.44-7.57(m, 2H), 7.74-7.85 (m, 2H).

Intermediate 4CV Tert-butyl3-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}azetidine-1-carboxylate

A mixture of Intermediate 3 (389 mg, 1.56 mmol), Intermediate 6CV (389mg, 1.56 mmol) and Cs₂CO₃ in DMF (11 mL) was stirred at 90° C. untilcomplete conversion. The DMF was evaporated under reduced pressure,water and DCM added, and the aqueous layer was extracted with DCM. Thecombined organics were evaporated to dryness. Crude material waspurified by column chromatography (silica gel, hexane/EtOAc gradient) togive 300 mg (46% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.38-1.44 (m, 9H), 2.90-3.05 (m, 1H),3.66-3.80 (m, 2H), 3.89 (s, 3H), 3.93-4.04 (m, 2H), 4.26 (d, 2H), 7.52(dd, 1H), 7.60-7.69 (m, 2H), 8.00 (t, 1H).

Intermediate 149N-[(2R)-1-(Benzyloxy)-3-hydroxypropan-2-yl]-2-chloroacetamide

(2R)-2-Amino-3-(benzyloxy)propan-1-ol (5.00 g, 27.6 mmol) was dissolvedin acetonitrile (87 mL) and MeOH (16 mL) and TEA (4.6 mL, 33 mmol) wasadded. The mixture was cooled to −10° C. and a solution of chloroacetylchloride (2.4 mL, 30 mmol) in acetonitrile was added dropwise. Themixture was stirred for 20 hours at RT. The solvent was evaporated underreduced pressure and the residue purified by silica gel columnchromatography (EtOAc/hexane gradient) to give 5.46 g (77% yield) of thetitle compound.

¹H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 2.57 (br. s., 1 H) 3.51-3.71 (m,3 H) 3.81 (dd, 1 H) 3.95-4.10 (m, 3 H) 4.42-4.52 (m, 2 H) 7.16 (d, 1 H)7.21-7.35 (m, 5 H).

Intermediate 150 (5S)-5-[(Benzyloxy)methyl]morpholin-3-one

To a solution of potassium tert-butoxide (980 mg, 8.73 mmol) in2-methylbutan-2-ol was added dropwise a solution of the Intermediate 149(2.25 g, 8.73 mmol) in 2-methylbutan-2-ol over two hours. After 12hours, an additional 1 equivalent of potassium tert-butoxide was addedand the reaction mixture stirred for 12 h. The solvent was distilled offunder reduced pressure and the residue purified by silica gel columnchromatography (EtOAc/EtOH gradient) to give 1.50 g (78% yield) of thetitle compound.

¹H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 3.39-3.48 (m, 1 H) 3.56 (dd, 1H) 3.63 (dd, 1 H) 3.70-3.81 (m, 1 H) 3.87 (dd, 1 H) 4.16 (d, 2 H) 4.55(d, 2 H) 6.33 (br. s., 1 H) 7.29-7.42 (m, 5 H).

Intermediate 151 (5S)-5-[(Benzyloxy)methyl]-4-methylmorpholin-3-one

A solution of Intermediate 150 (619 mg, 2.8 mmol) in THF (25 mL) wasadded dropwise to a suspension of NaH (134 mg, 60%, 3.36 mmol) in THF(70 mL) at 0° C. The mixture was stirred for 30 minutes at RT thencooled to 0° C. and MeI (870 μL, 14 mmol) added. After 15 mins thereaction mixture was warmed to RT and stirred for 15 hours. A saturatedaqueous solution of NH₄Cl (50 mL) was added at 0° C. and the solventevaporated at reduced pressure. The residue was diluted with water,extracted with EtOAc and the organic layer dried over MgSO₄. The solventwas distilled off under reduced pressure to give 650 mg (99% yield) ofthe title compound, which was used without further purification.

LCMS, method 1, rt: 0.90 min, MS ES+ m/z=236 (M+H)⁺.

Intermediate 152 (5S)-5-(Hydroxymethyl)-4-methylmorpholin-3-one

Intermediate 151 (617 mg, 2.62 mmol) was dissolved in EtOH, Pd(OH)₂ (92mg, 20% on carbon, 131 μmol) was added and stirred for 10 h underhydrogen atmosphere. Additional Pd(OH)₂ (0.025 eq.) was added and themixture stirred for 3 h under hydrogen atmosphere. The reaction mixturewas filtered through Celite® and washed with EtOH. The organic phaseconcentrated to dryness under reduced pressure to give 398 mg (100%yield) of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 1.96 (t, 1 H) 3.06 (s, 3 H) 3.29(td, 1 H) 3.79-3.96 (m, 3 H) 4.08-4.28 (m, 3 H).

Intermediate 6CX [(3R)-4-Methyl-5-oxomorpholin-3-yl]methyl4-methylbenzenesulfonate

A mixture of Intermediate 152 (322 mg, 2.22 mmol), TEA (460 μL, 3.3mmol) and trimethylamine hydrochloride in DCM was cooled to 0° C. andstirred for 10 minutes. 4-Methylbenzenesulfonyl chloride (465 mg, 2.44mmol) was added in 3 portions and the solution stirred at RT untilcomplete conversion. The reaction mixture was treated withN,N-dimethylethylenediamine (290 μL, 2.7 mmol) to consume the unreacted4-methylbenzenesulfonyl chloride. Water was added to the reactionmixture and the aqueous phase extracted with DCM. The organic phase wasconcentrated to dryness to give 505 mg (68% yield) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 2.43 (s, 3 H) 2.81 (s, 3 H) 3.54-3.62(m, 1 H) 3.75 (d, 2 H) 3.97 (s, 2 H) 4.15-4.25 (m, 2 H) 7.50 (d, 2 H)7.82 (d, 2 H).

Intermediate 4CX Methyl3-{[(3R)-4-methyl-5-oxomorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of Intermediate 3 (280 mg, 1.12 mmol), Intermediate 6CX (505mg, 1.69 mmol) and Cs₂CO₃ (550 mg, 1.69 mmol) was stirred at 90° C.until complete conversion. The DMF was evaporated under reducedpressure, water and DCM added, and the aqueous layer extracted with DCM(three times). The combined organics were evaporated to dryness and thecrude material purified by column chromatography (silica gel,hexane/EtOAc gradient) to give 530 mg of the title compound.

LCMS, method 1, rt: 1.09 min, MS ES+ m/z=377 (M+H)⁺.

Intermediate 153 (5S)-5-(Hydroxymethyl)morpholin-3-one

Intermediate 150 (650 mg, 2.94 mmol) was dissolved in MeOH (53 mL) andPd(OH)₂ (103 mg, 20% on carbon, 147 μmol) added and stirred for 8 hunder hydrogen atmosphere. The mixture was filtered through Celite®,washed with EtOH and the filtrate concentrated under reduced pressure togive 322 mg (74% yield) of the title compound, which was used withoutfurther purification.

¹H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 2.88 (br. s., 1 H) 3.59-3.79 (m,4 H) 3.82-3.97 (m, 1 H) 4.06-4.25 (m, 2 H) 7.18 (br. s., 1 H).

Intermediate 6CY [(3R)-5-Oxomorpholin-3-yl]methyl4-methylbenzenesulfonate

A mixture of Intermediate 153 (322 mg, 2.46 mmol), TEA (510 μL, 3.7mmol) and trimethylamine hydrochloride (23.5 mg, 246 μmol) in DCM (7.2mL) was cooled to 0° C. and stirred for 10 minutes.4-Methylbenzenesulfonyl chloride (515 mg, 2.70 mmol) was added in 3portions and the solution stirred at RT until complete conversion. Thereaction mixture was treated with N,N-Dimethylethylenediamine (320 μL,2.9 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Waterwas added to the crude mixture and the collected aqueous phase wasextracted with DCM (three times). The combined organic layers wereconcentrated to dryness to give 526 mg (42% yield) of the titlecompound, which was used without further purification.

LCMS, method 1, rt: 0.83 min, MS ES+ m/z=286 (M+H)⁺.

Intermediate 4CY Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3R)-5-oxomorpholin-3-yl]methoxy}benzoate

A mixture of Intermediate 3 (306 mg, 1.23 mmol), Intermediate 6CY (526mg, 1.84 mmol) and Cs₂CO₃ (601 mg, 1.84 mmol) in DMF (120 mL) wasstirred at 90° C. until complete conversion. DMF was evaporated underreduced pressure and the residue partitioned between water and DCM. Theaqueous layer was extracted with DCM (three times) and the combinedorganic layers evaporated to dryness. Purification by columnchromatography (silica gel, EtOAc/hexane gradient) gave 834 mg of thetitle compound.

LCMS, method 1, rt: 1.03 min, MS ES+ m/z=363 (M+H)⁺.

Intermediate 154 (2S)-3-[Benzyl(methyl)amino]propane-1, 2-diol

A solution of (2R)-oxiran-2-ylmethanol (4.71 g, 63.6 mmol) andN-methyl-1-phenylmethanamine (7.9 mL, 61 mmol) in MeOH (350 mL) washeated under reflux for 24 h, cooled to RT and evaporated to drynessunder reduced pressure to give 12.6 g of the title compound, which wasused without further purification.

LCMS, method 1, rt: 0.83 min, MS ES+ m/z=196 (M+H)⁺.

Intermediate 155 (2S)-3-(Methylamino)propane-1,2-diol

A mixture of Intermediate 154 (12.6 g, 64.5 mmol) and palladium oncarbon (4.12 g, 5%, 1.94 mmol) in MeOH (78 mL) was hydrogenated at 5 barfor 18 h at 23° C. The mixture was filtered, washed with MeOH and thefiltrate evaporated to dryness under reduced pressure to give 6.07 g(76% yield) of the title compound, which was used without furtherpurification.

¹H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 2.45 (s, 3 H) 2.63-2.70 (m, 1 H)2.71-2.77 (m, 1 H) 2.89-2.98 (m, 3 H) 3.54-3.62 (m, 1 H) 3.67-3.74 (m, 1H) 3.79 (ddt, 1 H).

Intermediate 156 (5S)-5-(Hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one

To a mixture of Intermediate 155 (3.25 g, 30.9 mmol) and diethylcarbonate (22 mL, 190 mmol) was added potassium tert-butoxide (173 mg,1.55 mmol). The reaction mixture was stirred for 14 h at 100° C. andevaporated to dryness to give 1.44 g (31% yield) of the title compound,which was used without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 2.72 (s, 3 H) 3.27 (dd, 1 H)3.41-3.49 (m, 1 H) 3.53 (t, 2 H) 4.46 (ddd, 1 H) 5.09 (s, 1 H).

Intermediate 6CZ [(5S)-3-Methyl-2-oxo-1,3-oxazolidin-5-yl]methyl4-methylbenzenesulfonate

A mixture of Intermediate 156 (2.24 g, 17.1 mmol), TEA (3.6 mL, 26 mmol)and trimethylamine hydrochloride (163 mg, 1.71 mmol) in DCM (50 mL) wasstirred at 0° C. for 10 minutes then treated with4-methylbenzenesulfonyl chloride in 3 portions. The mixture was stirredat RT until complete conversion. The reaction mixture was treated withN,N-dimethylethylenediamine (2.2 mL, 20 mmol) to consume unreacted4-methylbenzenesulfonyl chloride. Water was added, the aqueous phaseextracted with DCM (three times) and the combined organic layersconcentrated to dryness to give 4.67 g (91% yield) of the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 2.47 (s, 3 H) 2.87 (s, 3 H) 3.44(dd, 1 H) 3.65 (t, 1 H) 4.06-4.21 (m, 2 H) 4.61-4.73 (m, 1 H) 7.38 (d, 2H) 7.76-7.86 (m, 2 H).

Analytical chiral HPLC, method G: retention time: 5.04 min (78.4%) and5.48 min (21.6%), ee-value: 56.8%.

Intermediate 4CZ Methyl3-{[(5S)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of Intermediate 3 (582 mg, 2.34 mmol), Intermediate 6CZ (1.00g, 3.50 mmol) and Cs₂CO₃ (1.14 g, 3.50 mmol) in DMF (17 mL) was stirredat 90° C. until complete conversion. The DMF was evaporated underreduced pressure and the residue purified by column chromatography(silica gel, EtOAc/hexane gradient) to give 844 mg (94% yield) of thetitle compound.

LCMS, method 1, rt: 1.07 min, MS ES+ m/z=363 (M+H)⁺.

Intermediate 157 (2R)-3-[Benzyl(methyl)amino]propane-1,2-diol

A solution of (2S)-oxiran-2-ylmethanol (3.77 g, 50.9 mmol) andN-methyl-1-phenylmethanamine (6.3 mL, 49 mmol) in MeOH (280 mL) washeated under reflux for 24 h, cooled to RT and evaporated to drynessunder reduced pressure to give 9.72 g (98% yield) of the title compound,which was used without further purification.

LCMS, method 1, rt: 0.86 min, MS ES+ m/z=196 (M+H)⁺.

Intermediate 158 (2R)-3-(Methylamino)propane-1,2-diol

A mixture of Intermediate 157 (9.72 g, 49.8 mmol) and palladium oncarbon ((3.18 g, 5%, 1.49 mmol) in MeOH (60 mL) was hydrogenated at 5bar for 18 h at 23° C. The mixture was filtered, washed with MeOH andthe filtrate evaporated to dryness under reduced pressure to give 5.35 gof the title compound, which was used without further purification.

¹H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 2.43-2.47 (m, 3 H) 2.64-2.71 (m,1 H) 2.72-2.79 (m, 1 H) 2.91 (br. s., 3 H) 3.57-3.63 (m, 1 H) 3.68-3.75(m, 1 H) 3.76-3.83 (m, 1 H).

Intermediate 159 (5R)-5-(Hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one

To a solution of Intermediate 158 (2.58 g, 24.5 mmol) in diethylcarbonate (18 mL, 150 mmol) was added potassium tert-butoxide (138 mg,1.23 mmol). The reaction mixture was stirred for 24 h at 100° C. andevaporated to dryness. The residue was purified by column chromatography(silica gel, EtOAc/hexane gradient) to give 861 mg (27% yield) of thetitle compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 2.72 (s, 3 H) 3.27 (dd, 1 H) 3.47(dd, 1 H) 3.49-3.58 (m, 2 H) 4.40-4.51 (m, 1 H) 5.10 (t, 1 H).

Intermediate 6DA [(5R)-3-Methyl-2-oxo-1,3-oxazolidin-5-yl]methyl4-methylbenzenesulfonate

A mixture of Intermediate 159 (2.74 g, 20.9 mmol), TEA (4.4 mL, 31 mmol)and trimethylamine hydrochloride (200 mg, 2.09 mmol) in DCM (61 mL) wascooled to 0° C. and stirred for 10 minutes. 4-Methylbenzenesulfonylchloride (4.38 g, 23.0 mmol) was added in 3 portions and the solutionstirred at RT until complete conversion. The reaction mixture wastreated with N,N-dimethylethylenediamine (2.7 mL, 25 mmol) to consumeunreacted 4-methylbenzenesulfonyl chloride. Water was added, the aqueousphase extracted with DCM (three times) and the combined organic layersconcentrated to dryness to give 5.97 g (94% yield) of the titlecompound, which was used without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.43 (s, 3 H) 2.66-2.73 (m, 3 H) 3.17(dd, 1 H) 3.57 (t, 1 H) 4.09-4.17 (m, 1 H) 4.18-4.25 (m, 1 H) 4.69 (dt,1 H) 7.47-7.55 (m, 2 H) 7.75-7.85 (m, 2 H).

Analytical chiral HPLC, method G: retention time: 5.46 min (88.0%) and5.05 min (12.0%), ee-value: 76.0%.

Intermediate 4DA Methyl3-{[(5R)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of Intermediate 6DA (582 mg, 2.34 mmol), Intermediate 3 (1.00g, 3.50 mmol) and Cs₂CO₃ (1.14 g, 3.50 mmol) in DMF (17 mL) was stirredat 90° C. until complete conversion. The DMF was evaporated underreduced pressure, water and DCM were added and the aqueous layerextracted with DCM (three times). The combined organic layers wereevaporated to dryness under reduced pressure. The residue was purifiedby column chromatography (silica gel, EtOAc/hexane gradient) to give 609mg (67% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.79 (s, 3 H) 3.33 (s, 2 H) 3.43 (dd, 1H) 3.70 (t, 1 H) 3.89 (s, 3 H) 4.22-4.31 (m, 1 H) 4.32-4.40 (m, 1 H)4.82-4.93 (m, 1 H) 7.53 (dd, 1 H) 7.66 (q, 2 H) 8.02 (t, 1 H).

Intermediate 160 2-Chloro-N-[(2R)-2,3-dihydroxypropyl]-N-methylacetamide

To a solution of Intermediate 158 (2.80 g, 26.6 mmol) in acetonitrile(84 mL) and MeOH (16 mL) was added TEA (4.5 mL, 32 mmol) and the mixturecooled to −10° C. A solution of chloroacetyl chloride (2.3 mL, 29 mmol)in acetonitrile was added dropwise and the mixture stirred for 20 hoursat RT. The reaction solvent was distilled off to give 4.53 g (94% yield)of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.45 min, MS ES+ m/z=183 (M+H)⁺.

Intermediate 161 (6R)-6-(Hydroxymethyl)-4-methylmorpholin-3-one

To a solution of potassium tert-butoxide (5.60 g, 49.9 mmol) in2-methylbutan-2-ol was added dropwise a solution of the Intermediate 160(4.53 g, 24.9 mmol) in 2-methylbutan-2-ol over two hours. After 4 hoursconversion was complete. The solvent was distilled off under reducedpressure and the residue purified by silica gel column chromatography(EtOAc/EtOH gradient) to give 4.63 g of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 2.85 (s, 3 H) 3.21-3.27 (m, 2 H)3.37-3.54 (m, 2 H) 3.78 (dq, 1 H) 4.01-4.06 (m, 2 H) 4.91 (t, 1 H).

Intermediate 6DB [(2R)-4-Methyl-5-oxomorpholin-2-yl]methyl4-methylbenzenesulfonate

A mixture of Intermediate 161 (4.63 g, 31.9 mmol), TEA (6.7 mL, 48 mmol)and trimethylamine hydrochloride (305 mg, 3.19 mmol) in DCM (94 mL) wascooled to 0° C. and stirred for 10 minutes. After that4-methylbenzenesulfonyl chloride (6.69 g, 35.1 mmol) was added in 3portions. The solution was stirred at RT until complete conversion. Thereaction mixture was treated with N,N-dimethylethylenediamine (4.2 mL,38 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Waterwas added, the aqueous phase extracted with DCM (three times) and theorganic layer concentrated to dryness to give 3.43 g (36% yield) of thetitle compound, which was used without further purification.

LCMS, method 1, rt: 0.90 min, MS ES+ m/z=300 (M+H)⁺.

Intermediate 4DB Methyl3-{[(2R)-4-methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of Intermediate 3 (1.90 g, 7.64 mmol), Intermediate 6DB (3.43g, 11.5 mmol), and Cs₂CO₃ (3.73 g, 11.5 mmol) in DMF (56 mL) was stirredat 90° C. until complete conversion. The DMF was evaporated underreduced pressure to give 2.76 g (96% yield) of the title compound, whichwas used without further purification.

LCMS, method 1, rt: 1.06 min, MS ES+ m/z=377 (M+H)⁺.

Intermediate 162 2-Chloro-N-[(2S)-2,3-dihydroxypropyl]acetamide

(2S)-3-Aminopropane-1,2-diol (5.00 g, 54.9 mmol) was dissolved inacetonitrile (170 mL) and MeOH (32 mL) and TEA (9.2 mL, 66 mmol) wasadded. The mixture was cooled to −10° C. and a solution of chloroacetylchloride (4.8 mL, 60 mmol) in acetonitrile, was added dropwise, and themixture was stirred for 21 hours at RT. The reaction solvent wasdistilled off under reduced pressure and the remaining residue waspurified by column chromatography (silica gel, EtOAc/hexane/MeOHgradient) to give 10.5 g of the title compound.

Intermediate 163 (65)-6-(Hydroxymethyl)morpholin-3-one

Potassium tert-butoxide (14.0 g, 125 mmol) was dissolved in2-methylbutan-2-ol. A solution of the Intermediate 162 in2-methylbutan-2-ol was added dropwise over two hours and the reactionmixture stirred until complete conversion. The solvent was distilled offunder reduced pressure and the residue was purified by columnchromatography (silica gel, EtOAc/hexane gradient) to give 7.46 g (27%yield).

Intermediate 6DC [(2S)-5-Oxomorpholin-2-yl]methyl4-methylbenzenesulfonate

A mixture of Intermediate 163 (7.46 g, 56.9 mmol), TEA (12 mL, 85 mmol)and trimethylamine hydrochloride (544 mg, 5.69 mmol) in DCM was cooledto 0° C. and stirred for 10 minutes. After that 4-methylbenzenesulfonylchloride (11.9 g, 62.6 mmol) was added in 3 portions. The solution wasstirred at RT until complete conversion. The reaction mixture wastreated with N,N-dimethylethylenediamine (7.5 mL, 68 mmol) to consumeunreacted 4-methylbenzenesulfonyl chloride. Water was added, the aqueousphase extracted with DCM (three times) and the organic layer wasconcentrated to dryness under reduced pressure to give 5.23 g of thetitle compound, which was used without further purification.

LCMS, method 1, rt: 0.86 min, MS ES+ m/z=286 (M+H)⁺.

Intermediate 4DC Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-{[(2S)-5-oxomorpholin-2-yl]methoxy}benzoate

A mixture of Intermediate 3 (3.05 g, 12.2 mmol), Intermediate 6DC (5.23g, 18.3 mmol), and Cs₂CO₃ (5.97 g, 18.3 mmol) in DMF (89 mL) was stirredat 90° C. until complete conversion. The DMF was evaporated and DCM andwater was added. The mixture was extracted with DCM (three times), thecombined organic layers evaporate to dryness under reduced pressure andthe residue purified by silica gel column chromatography (EtOAc/EtOHgradient) to give 2.14 g (48% yield) of the title compound.

LCMS, method 1, rt: 1.00 min, MS ES+ m/z=363 (M+H)⁺.

Intermediate 164 2-Chloro-N-[(2S)-2,3-dihydroxypropyl]-N-methylacetamide

Intermediate 155 was dissolved in acetonitrile (84 mL) and MeOH (16 mL)and TEA (4.5 mL, 32 mmol) was added and the mixture was cooled to −10°C. A solution of chloroacetyl chloride (2.3 mL, 29 mmol) in acetonitrilewas added dropwise and the mixture was stirred for 20 hours at RT. Thesolvent was distilled off under reduced pressure to give 8.64 g of thetitle compound, which was used without further purification.

Intermediate 165 (65)-6-(Hydroxymethyl)-4-methylmorpholin-3-one

Potassium tert-butoxide (8.01 g, 71.4 mmol) was dissolved in2-methylbutan-2-ol. A solution of Intermediate 164 in 2-methylbutan-2-olwas added dropwise over two hours. The mixture was stirred overnight andthen the reaction solvent was distilled off under reduced pressure togive 3.63 g (53% yield) of the title compound, which was used withoutfurther purification.

Intermediate 6DD [(2S)-4-Methyl-5-oxomorpholin-2-yl]methyl4-methylbenzenesulfonate

A mixture of Intermediate 165 (4.00 g, 27.6 mmol), TEA (5.8 mL, 41 mmol)and trimethylamine hydrochloride (263 mg, 2.76 mmol) in DCM (81 mL) wascooled to 0° C. and stirred for 10 minutes. After that4-methylbenzenesulfonyl chloride (5.78 g, 30.3 mmol) was added in 3portions. The solution was stirred at RT until complete conversion. Thereaction mixture was treated with N,N-dimethylethylenediamine (3.6 mL,33 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Waterwas added, and the aqueous phase was extracted with DCM (three times)and the combined organic layers were concentrated to dryness. Theresidue was purified by column chromatography (silica gel, EtOAc/MeOHgradient) to give 2.55 g (31% yield) of the title compound.

LCMS, method 1, rt: 0.90 min, MS ES+ m/z=300 (M+H)⁺.

Intermediate 4DD Methyl3-{[(2S)-4-methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of Intermediate 3 (1.42 g, 5.68 mmol), Intermediate 6DD (2.55g, 8.52 mmol), and Cs₂CO₃ (2.78 g, 8.52 mmol) in DMF (41 mL) was stirredat 90° C. until complete conversion. The DMF was destilled off underreduced pressure and the residue was purified by column chromatography(silica gel, EtOAc/hexane gradient) to give 1.57 g (73% yield) of thetitle compound.

LCMS, method 1, rt: 1.06 min, MS ES+ m/z=377 (M+H)⁺.

Intermediate 166N-[(2S)-1-(Benzyloxy)-3-hydroxypropan-2-yl]-2-chloroacetamide

(2S)-2-Amino-3-(benzyloxy)propan-1-ol (5.00 g, 27.6 mmol) was dissolvedin acetonitrile (87 mL), MeOH (16 mL) and TEA (4.6 mL, 33 mmol) wasadded. The mixture was cooled to −10° C. and a solution of chloroacetylchloride (2.4 mL, 30 mmol) in acetonitrile was added dropwise. Themixture was stirred for 20 hours at RT and the reaction solvents weredistilled off to give 10.91 g of the title compound, which was usedwithout further purification.

LCMS, method 1, rt: 0.83 min, MS ES+ m/z=258 (M+H)⁺.

Intermediate 167 (5R)-5-[(Benzyloxy)methyl]morpholin-3-one

Potassium tert-butoxide (3.96 g, 35.3 mmol) was dissolved in2-methylbutan-2-ol. A solution of the Intermediate 166 (5.68 g, 17.6mmol) in 2-methylbutan-2-ol (160 mL in total) was added dropwise overtwo hours and the mixture was stirred until complete conversion. Thereaction solvent was distilled off under reduced pressure and theresidue was purified by silica gel column chromatography (EtOAc/EtOHgradient) to give 3.57 g (89% yield) of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 3.39-3.47 (m, 1 H) 3.56 (dd, 1H) 3.63 (dd, 1 H) 3.71-3.81 (m, 1 H) 3.87 (dd, 1 H) 4.09-4.24 (m, 2 H)4.49-4.60 (m, 2 H) 6.39 (br. s., 1 H) 7.29-7.43 (m, 5 H).

Intermediate 168 (5R)-5-[(Benzyloxy)methyl]-4-methylmorpholin-3-one

A solution of Intermediate 167 (2.00 g, 9.04 mmol) in THF (25 mL) wasadded dropwise to a suspension of NaH (434 mg, 60% purity, 10.8 mmol) inTHF (70 mL) at 0° C. The mixture was stirred for 30 minutes at RT. Tothe mixture, MeI (2.8 mL, 45 mmol) was added at 0° C., and the mixturewas stirred for 15 hours at room temperature. A saturated aqueoussolution (50 mL) of NH₄Cl was added at 0° C., and the solvents weredistilled off under reduced pressure. The residue was diluted with waterand extracted with EtOAc (three times). The combined organic layers weredried over MgSO₄ and the solvent distilled off under reduced pressure togive 1.78 g (78% yield) of the title compound.

¹H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 3.03 (s, 3 H) 3.40 (ddd, 1 H)3.62-3.81 (m, 3 H) 4.03-4.24 (m, 3 H) 4.51-4.61 (m, 2 H) 7.29-7.41 (m, 5H).

Intermediate 169 (5R)-5-(Hydroxymethyl)-4-methylmorpholin-3-one

Intermediate 168 (1.78 g, 7.57 mmol) was dissolved in MeOH (140 mL),Pd(OH)₂ (266 mg, 20% on carbon, 378 μmol) was added and the mixturestirred for 10 hours under a hydrogen atmosphere. Another 0.0025equivalents catalyst was added and and the mixture stirred foradditional 3 hours under a hydrogen atmosphere. The reaction mixture wasfiltered through Celite® and washed with EtOH and the filtrate underreduced pressure to give 1.12 g of the title compound, which was usedwithout further purification.

Intermediate 6DE [(3S)-4-Methyl-5-oxomorpholin-3-yl]methyl4-methylbenzenesulfonate

A mixture of Intermediate 169, TEA (1.6 mL, 12 mmol) and trimethylaminehydrochloride (73.7 mg, 772 μmol) in DCM (23 mL) was cooled to 0° C. andstirred for 10 minutes. After that 4-methylbenzenesulfonyl chloride(1.62 g, 8.49 mmol) was added in 3 portions. The solution was stirred atRT until complete conversion. The reaction mixture was treated withN,N-dimethylethylenediamine (1.0 mL, 9.3 mmol) to consume unreacted4-methylbenzenesulfonyl chloride. Water was added to the mixture and thephases separated. The aqueous phase was extracted with DCM (three times)and the combined organic layers concentrated to dryness. The residue waspurified by column chromatography (silica gel, EtOAc/hexane gradient) togive 917 mg (40% yield) of the title compound.

LCMS, method 1, rt: 0.89 min, MS ES+ m/z=300 (M+H)⁺.

Intermediate 4DE Methyl3-{[(3S)-4-methyl-5-oxomorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of Intermediate 3 (312 mg, 1.25 mmol), Intermediate 6DE (450mg, 1.50 mmol) and Cs₂CO₃ (612 mg, 1.88 mmol) in DMF (6.3 mL) wasstirred at 90° C. until complete conversion. The DMF was distilled offunder reduced pressure, water and DCM was added and the layersseparated. The aqueous layer was extracted with DCM (three times) andthe combined organic layers were evaporated to dryness. The residue waspurified by column chromatography (silica gel, EtOAc/hexane gradient) togive 294 mg (58% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 3.00 (s, 3 H) 3.71-3.79 (m, 1 H)3.83-3.92 (m, 4 H) 4.01 (d, 1 H) 4.08 (d, 2 H) 4.29 (d, 1 H) 4.33-4.42(m, 1 H) 7.57 (dd, 1 H) 7.66 (d, 1 H) 7.70 (dd, 1 H) 8.02 (t, 1 H).

Intermediate 170 (5R)-5-(Hydroxymethyl)morpholin-3-one

Intermediate 167 was dissolved in MeOH (120 mL), Pd(OH)₂ (244 mg, 20% oncarbon, 348 μmol) added and stirred for 10 h under a hydrogenatmosphere. Another 0.025 equivalents catalyst was added and the mixturewas stirred for additional 3 hours. The reaction mixture was filteredthrough Celite® and washed with EtOH. The filtrate was concentratedunder reduced pressure to afford 1.16 g of the title compound, which wasused without further purification.

Intermediate 6DF [(3S)-5-Oxomorpholin-3-yl]methyl4-methylbenzenesulfonate

A mixture of Intermediate 170 (1.16 g, 8.85 mmol), TEA (1.8 mL, 13 mmol)and trimethylamine hydrochloride (84.5 mg, 885 μmol) in DCM (26 mL) wascooled to 0° C. and stirred for 10 minutes. After that4-methylbenzenesulfonyl chloride (1.86 g, 9.73 mmol) was added in 3portions. The solution was stirred at RT until complete conversion. Thereaction mixture was treated with N,N-dimethylethylenediamine (1.2 mL,11 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Waterwas added to the mixture, the layers separated and the aqueous phaseextracted with DCM (three times). The combined organic layers wereconcentrated to dryness and the residue was purified by silica gelcolumn chromatography (hexane/EtOAc/MeOH gradient) to give 1.06 g (42%yield) of the title compound.

LCMS, method 1, rt: 0.83 min, MS ES+ m/z=286 (M+H)⁺.

Intermediate 4DF Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3S)-5-oxomorpholin-3-yl]methoxy}benzoate

A mixture of Intermediate 3 (364 mg, 1.46 mmol), Intermediate 6DF (500mg, 1.75 mmol) and Cs₂CO₃ (714 mg, 2.19 mmol) was stirred at 90° C.until complete conversion. The DMF was evaporated under reducedpressure, water and DCM was added and the layers separated. The aqueouslayer was extracted with DCM (three times) and the combined organiclayers were evaporated to dryness. The residue was purified by silicagel column chromatography (hexane/EtOAc/MeOH gradient) to give 349 mg(59% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 3.76 (d, 1 H) 3.84-3.88 (m, 2 H) 3.89(s, 3 H) 4.01 (s, 2 H) 4.08 (dd, 1 H) 4.20 (dd, 1 H) 7.55 (dd, 1 H)7.63-7.72 (m, 2 H) 7.98-8.05 (m, 1 H) 8.30 (d, 1 H).

Intermediate 6DJ tert-Butyl1-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate,as a Mixture of Two Enantiomers

A mixture of tert-butyl1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (1.00g, 4.36 mmol), TEA (910 μL, 6.5 mmol) and trimethylamine hydrochloride(41.7 mg, 436 μmol) in DCM (13 mL) was cooled to 0° C. and stirred for10 minutes. After that 4-methylbenzenesulfonyl chloride (915 mg, 4.80mmol) was added in 3 portions and the solution stirred at RT overnight.The reaction mixture was treated with N,N-dimethylethylenediamine (570μL, 5.2 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride.Water was added to the mixture, the aqueous phase extracted with DCM(three times) and the combined organic layers concentrated to drynessunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/EtOAc/MeOH gradient) to give 1.41 g (84% yield)of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.38 (d, 9 H) 1.63-1.82 (m, 2 H) 2.43(s, 3 H) 3.04-3.24 (m, 2 H) 3.66 (s, 2 H) 4.37 (d, 3 H) 7.49 (d, 2 H)7.75-7.85 (m, 2 H).

Intermediate 4DG tert-Butyl1-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate,as a mixture of two Enantiomers

A mixture of Intermediate 3 (450 mg, 1.81 mmol), Intermediate 6DJ,Cs₂CO₃ (882 mg, 2.71 mmol) and DMF (10 mL) was stirred at 90° C. untilcomplete conversion. The DMF was evaporated under reduced pressure, theresidue was dissolved in water and DCM and the phases separated. Theaqueous layer was extracted twice with DCM. The combined organic layerswere evaporated to dryness under reduced pressure and the residue waspurified by silica gel column chromatography (hexane/EtOAc gradient) togive 635 mg (69% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.35-1.47 (m, 9 H) 1.84-1.96 (m, 2 H)3.35-3.48 (m, 2 H) 3.70-3.79 (m, 1 H) 3.81-3.92 (m, 4 H) 4.34-4.57 (m, 3H) 7.55 (dd, 1 H) 7.64-7.72 (m, 2 H) 8.01 (t, 1 H).

Intermediate 171 Methyl3-(5-methyl-1,3-thiazol-2-yl)-5-(2-oxa-5-azabicyclo[2.2.1]hept-1-ylmethoxy)benzoate,as a Mixture of Two Enantiomers

A mixture of Intermediate 4DG, TFA (4.4 mL, 57 mmol) and DCM (44 mL) wasstirred at RT until complete conversion. The mixture was evaporated todryness under reduced pressure to give 530 mg of the title compound,which was used without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 2.02 (m, 1 H) 2.12 (m, 1 H) 3.35 (t,2 H) 3.85-3.93 (m, 4 H) 3.97-4.18 (m, 2 H) 4.45 (br. s., 1 H) 4.50-4.67(m, 2 H) 7.56 (dd, 1 H) 7.64-7.76 (m, 2 H) 8.02 (t, 1 H).

Intermediate 173 Methyl3-[(5-methyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate,as a Mixture of Two enantiomers

A mixture of Intermediate 171 (257 mg, 712 μmol), formaldehyde (530 μL,37%, 7.1 mmol), acetic acid (410 μL, 100%, 7.1 mmol) and1,2-dichlorethane (6.1 mL) was stirred at RT for 30 min. After thatsodium triacetoxyborohydride was added (3.0 mL, 2.1 mmol) carefully andthe mixture stirred at RT. Additional amounts of formaldehyde, aceticacid and sodium triacetoxyborohydride were added to drive the reactionto completion. A saturated aqueous NaHCO₃-solution was added and theaqueous layer extracted twice with DCM. The combined organic layers wereevaporated to dryness under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/EtOAc gradient) to give 100mg (38% yield) of the title compound.

¹H NMR (600 MHz, DMSO-d₆): δ [ppm] 1.68-1.75 (m, 1 H) 1.84-1.92 (m, 1 H)2.34 (s, 3 H) 2.90-2.97 (m, 1 H) 3.36-3.41 (m, 1 H) 3.62-3.68 (m, 1 H)3.89 (s, 3 H) 3.96-4.01 (m, 1 H) 4.37 (s, 1 H) 4.41 (s, 1 H) 7.48-7.57(m, 1 H) 7.66 (d, 2 H) 8.01 (s, 1 H).

Intermediate 174 Methyl3-[(5-isopropyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate,as a mixture of two enantiomers

Intermediate 174 (150 mg, 54%) was synthesised from Intermediate 171(250 mg, 694 μmol) and acetone (200 μL, 2.8 mmol) in analogy to theconversion of Intermediate 171 to Intermediate 173.

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 0.96-1.07 (m, 6 H) 1.70-1.85 (m, 2 H)2.61-2.77 (m, 1 H) 3.05-3.20 (m, 1 H) 3.60-3.75 (m, 2 H) 3.89 (s, 3 H)3.99 (d, 1 H) 4.30-4.47 (m, 2 H) 7.53 (dd, 1 H) 7.63-7.70 (m, 2 H) 8.00(t, 1 H).

Intermediate 5CF3-{[4-(Tert-butoxycarbonyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, as a mixture of enantiomers

Intermediate 4CF (331 mg, 0.59 mmol) was dissolved in MeOH (5 mL) andTHF (5 mL). 1M LiOH (2 mL) was added and the reaction stirred at RT for2 h. The reaction mixture was concentrated to dryness and the residuetaken up in water (5 mL) and washed with EtOAc (5 mL). The aqueous layerwas acificied to pH 4 with 1M HCl and extracted with DCM (2×5 mL) and1:1 IPA/CHCl₃ (2×5 mL). The combined organics were dried (MgSO₄),filtered and concentrated under reduced pressure. The residue was takenup in MeCN/water and freeze-dried to give 231.2 mg (85% yield) of thetitle compound as white powder.

¹H NMR (250 MHz, DMSO-d): δ [ppm] 7.99 (s, 1H), 7.67-7.63 (m, 1H),7.63-7.59 (m, 1H), 7.53-7.48 (m, 1H), 4.24-4.07 (m, 2H), 3.99-3.81 (m,2H), 3.79-3.65 (m, 2H), 3.53-3.40 (m, 1H), 3.00-2.79 (m, 2H), 1.41 (s,9H).

LC-MS (Method A) Rt=1.36 min, MS (ESIpos): m/z=435 (M+H)⁺.

Intermediate 5CE3-{[(2R)-4-(tert-butoxycarbonyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

Intermediate 4CE (27.2 g, 48.6 mmol) was dissolved in THF (200 mL). 1MLiOH (100 mL, 100 mmol) was added and the reaction stirred at RT for 2h. Further THF (50 mL), 1M LiOH (50 mL, 50 mmol) and methanol (20 mL)was added and the reaction mixture stirred at RT for 1 h. The reactionmixture was concentrated to remove MeOH/THF and the aqueous layer washedwith EtOAc. The aqueous layer was acificied to pH 4 with conc. HCl andextracted with DCM (3×100 mL). The combined DCM and EtOAc organics weredried (MgSO₄), filtered and concentrated under reduced pressure to give28.21 g (94% yield) of the title compound as yellow viscous oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.23 (s, 1H), 7.65 (s, 2H), 7.54(s, 1H), 4.27-3.48 (m, 7H), 3.11-2.77 (m, 2H), 2.50 (s, 3H), 1.47 (s,9H).

LCMS (Method A) Rt=1.23 min, MS (ESIpos): m/z=435 (M+H)⁺.

In analogy to the procedure described for Intermediate 5CF, thefollowing Intermediates were prepared using the corresponding esterstarting materials.

Int. Structure Name Analytical Data 5CG

3-{[1-(tert- butoxy- carbonyl) piperidin-4- yl]methoxy}-5-(5-methyl-1,3- thiazol-2- yl)benzoic acid ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 8.22 (t, J = 1.3, 1H), 7.74- 7.68 (m, 1H), 7.63(dd, J = 2.4, 1.3, 1H), 7.58 (d, J = 1.1, 1H), 4.17 (s, 2H), 3.94 (d, J= 6.4, 2H), 2.86- 2.69 (m, 2H), 2.54 (d, J = 0.9, 3H), 2.04-1.95 (m,1H), 1.91-1.79 (m, 2H), 1.48 (s, 9H), 1.38-1.25 (m, 2H). LC-MS (MethodA) Rt = 1.29 min, MS (ESIpos): m/z = 433 (M + H)⁺. 5CD

3-{[(2S)-4- (tert- butoxy- carbonyl) morpholin-2- yl]methoxy}-5-(5-methyl-1,3- thiazol-2- yl)benzoic acid LC-MS (Method A) Rt = 1.20min, MS (ESIpos) m/z = 435 (M + H)⁺. 5CH

3-{[(2R)-4- (tert- butoxy- carbonyl) morpholin-2- yl]methoxy}-5-(5-ethyl-1,3- thiazol-2- yl)benzoic acid ¹H NMR (500 MHz, DMSO-d6): δ[ppm] 1.29 (t, J = 7.5 Hz, 3H), 1.41 (s, 9H), 2.73-3.00 (m, 4H), 3.46(td, J = 11.6, 2.7 Hz, 1H), 3.67- 3.76 (m, 2H), 3.82-3.96 (m, 2H),4.11-4.22 (m, 2H), 7.51 (dd, J = 2.4, 1.3 Hz, 1H), 7.63-7.65 (m, 1H),7.68-7.69 (m, 1H), 8.00 (t, J = 1.4 Hz, 1H), 13.23 (s, 1H). LC-MS(Method A) Rt = 1.31 min, MS (ESIpos): m/z = 449 (M + H)⁺. 5Cl

3-{[(2S)-4- (tert- butoxy- carbonyl) morpholin-2- yl]methoxy}-5-(5-ethyl-1,3- thiazol-2- yl)benzoic acid ¹H NMR (500 MHz, DMSO-d6): δ[ppm] 1.29 (td, J = 7.5, 3.0 Hz, 3H), 1.41 (s, 9H), 2.90 (m, 4H), 3.46(td, J = 11.6, 2.8 Hz, 1H), 3.66-3.78 (m, 2H), 3.82-3.98 (m, 2H),4.11-4.23 (m, 2H), 7.51 (dd, J = 2.4, 1.4 Hz, 1H), 7.61-7.64 (m, 1H),7.68 (s, 1H), 8.00 (t, J = 1.3 Hz, 1H), 13.27 (s, 1H). LC-MS (Method A)Rt = 1.33 min, MS (ESIpos): m/z = 449 (M + H)⁺. 5CJ

3-[[(2S)-4-tert- butoxy- carbonyl- morpholin-2- yl]methoxy]-5-(5-chloro- thiazol- 2-yl)benzoic acid ¹H NMR (500 MHz, chloroform-d): δ[ppm] 8.14 (s, 1H), 7.73-7.69 (m, 2H), 7.68 (s, 1H), 4.29-4.06 (m, 3H),4.06-3.74 (m, 3H), 3.63 (td, J = 11.5, 2.3 Hz, 1H), 3.14-2.97 (m, 1H),2.97-2.79 (m, 1H), 1.49 (s, 9H). LC-MS (Method A) Rt = 1.32 min, MS(ESIpos): m/z = 455 (M + H)⁺. 5CK

3-[[(2R)-4- tert- butoxy- carbonyl- morpholin-2- yl]methoxy]- 5-(5-chlorothiazol- 2-yl)benzoic acid ¹H NMR (500 MHz, chloroform-d): δ [ppm]8.14 (t, J = 1.4 Hz, 1H), 7.72- 7.69 (m, 2H), 7.68 (s, 1H), 4.22- 4.07(m, 3H), 4.03-3.73 (m, 3H), 3.71-3.51 (m, 1H), 3.10-2.97 (m, 1H),2.96-2.83 (m, 1H), 1.49 (s, 9H). LC-MS (Method A) Rt = 1.37 min, MS(ESIpos): m/z = 455 (M + H)⁺. 5CL

3-{[1-(tert- butoxy- carbonyl)-3- fluoroazetidin- 3-yl]methoxy}-5-(5-methyl- 1,3-thiazol-2- yl)benzoic acid ¹H NMR (500 MHz, DMSO-d6): δ[ppm] 1.40 (s, 9H), 2.51 (s, 3H), 3.97-4.08 (m, 2H), 4.15 (dd, J = 18.1,10.2 Hz, 2H), 4.53 (d, J = 22.0 Hz, 2H), 7.55 (dd, J = 2.5, 1.3 Hz, 1H),7.63-7.67 (m, 2H), 8.02 (t, J = 1.4 Hz, 1H), 13.32 (s, 1H). LC-MS(Method A) Rt =1.24 min, MS (ESIpos): m/z = 423 (M + H)⁺.

Intermediate 5CV3-{[1-(tert-Butoxycarbonyl)azetidin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

A mixture of Intermediate 4CV (100 mg, 239 μmol), NaOH (600 μL, 2.0 M,1.2 mmol) in MeOH (20 mL) was stirred at RT until complete conversion.The MeOH was evaporated and aqueous Ha-solution (2N) was added and thepH adjusted to pH 4. The aqueous layer was extracted with DCM. Thecombined organics were evaporated to dryness to give 95 mg (98% yield)of the title compound, which was used without further purification.

LCMS, method 1, rt: 1.28 min, MS ES+ m/z=405 (M+H)⁺.

Intermediate 5CX3-{[(3R)-4-Methyl-5-oxomorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a solution of Intermediate 4CX (530 mg, 1.41 mmol) in MeOH was addedan aqueous NaOH-solution (1.8 mL, 2.0 M, 3.5 mmol). The mixture wasstirred at RT until complete conversion. The reaction mixture wasconcentrated under reduced pressure and the pH adjusted to pH: 5. Themixture was extracted three times with EtOAc and the combined organiclayers evaporated to dryness to give 417 mg (82% yield) of the titlecompound.

LCMS, method 1, rt: 0.90 min, MS ES+ m/z=363 (M+H)⁺.

Intermediate 5CY3-(5-Methyl-1,3-thiazol-2-yl)-5-{[(3R)-5-oxomorpholin-3-yl]methoxy}benzoicacid

To a solution of Intermediate 4CY (834 mg, 50% purity, 1.15 mmol) inMeOH was added an aqueous NaOH solution (1.4 mL, 2.0 M, 2.9 mmol). Themixture was stirred at RT for 15 h, another 1 mL aqueous NaOH solution(2.0 M) was added and the mixture stirred at RT until completeconversion. The reaction mixture was concentrated under reduced pressureand the pH adjusted to pH: 5. The mixture was extracted three times withEtOAc and the combined organic layers evaporated to dryness to give 466mg of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.84 min, MS ES+ m/z=349 (M+H)⁺.

Intermediate 5CZ3-{[(5S)-3-Methyl-2-oxo-1,3-oxazolidin-5-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a mixture of Intermediate 4CZ in MeOH (15 mL) was added an aqueousNaOH solution (2.9 mL, 2.0 M, 5.8 mmol). The mixture was stirred at RTuntil complete conversion. The solvent was evaporated under reducedpressure and the pH adjusted to pH 5. The mixture was extracted threetimes with EtOAc and the organic layer evaporated to dryness to give 617mg (83% yield) of the title compound, which was used without furtherpurification.

LCMS, method 1, rt: 0.93 min, MS ES+ m/z=349 (M+H)⁺.

Intermediate 5DA3-{[(5R)-3-Methyl-2-oxo-1,3-oxazolidin-5-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a solution of Intermediate 4DA (609 mg, 1.68 mmol) in MeOH (6.4 mL)and THF (6.4 mL) was added an aqueous NaOH solution (2.1 mL, 2.0 M, 4.2mmol). The mixture was stirred at RT until complete conversion. Themixture was concentrated under reduced pressure and the pH adjusted topH: 3. Then the mixture was extracted three times with EtOAc and theorganic layers evaporated to dryness under reduced pressure to give 518mg (87% yield) of the title compound, which was used without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 2.79 (s, 3 H) 3.43 (dd, 1 H) 3.70 (t,1 H) 4.22-4.30 (m, 1 H) 4.31-4.38 (m, 1 H) 4.82-4.93 (m, 1 H) 7.53 (dd,1 H) 7.60-7.69 (m, 2 H) 8.00 (t, 1 H) 13.00-13.56 (m, 1 H).

Intermediate 5DB3-{[(2R)-4-Methyl-5-oxomorpholin-2-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a mixture of Intermediate 4DB in MeOH (28 mL) and THF (28 mL) wasadded an aqueous NaOH solution (9.2 mL, 2.0 M, 18 mmol). The mixture wasstirred at RT until complete conversion. The mixture was concentratedunder reduced pressure and the pH adjusted to pH: 3. The mixture wasextracted three times with EtOAc, the combined organic layers were drieddown under reduced pressure and the residue purified by columnchromatography (silica gel, EtOAc/hexane gradient) to give 1.65 g (59%yield) of the title compound.

LCMS, method 1, rt: 0.91 min, MS ES+ m/z=363 (M+H)⁺.

Intermediate 5DC3-(5-Methyl-1,3-thiazol-2-yl)-5-{[(2S)-5-oxomorpholin-2-yl]methoxy}benzoicacid

To a mixture of Intermediate 4DC in MeOH (38 mL) and THF (38 mL) wasadded an aqueous NaOH solution (7.4 mL, 2.0 M, 15 mmol). The mixture wasstirred at RT until complete conversion. The mixture was extracted withEtOAc and the phases separated. The aqueous layer was extracted threetimes with EtOAc and the combined organic layers were evaporated todryness under reduced pressure to give 434 mg (21% yield) of the titlecompound

LCMS, method 1, rt: 0.77 min, MS ES+ m/z=349 (M+H)⁺.

Intermediate 5DD3-{[(2S)-4-Methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a solution of Intermediate 4DD (1.57 g, 4.17 mmol) in MeOH (10 mL)and THF (10 mL) was added an aqueous NaOH solution (3.1 mL, 2.0 M, 6.3mmol). The mixture was stirred at RT until complete conversion. Themixture was concentrated under reduced pressure and extracted threetimes with EtOAc. The combined organic layers were evaporated to drynessunder reduced pressure to give 2.24 g of the title compound, which wasused without further purification.

LCMS, method 1, rt: 0.87 min, MS ES+ m/z=363 (M+H)⁺.

Intermediate 5DE3-{[(3S)-4-Methyl-5-oxomorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a mixture of Intermediate 4DE in MeOH was added an aqueous NaOHsolution (980 μL, 2.0 M, 2.0 mmol). The mixture was stirred at RT untilcomplete conversion. The pH was adjusted to pH: 5, the reaction mixtureextracted with

EtOAc, the organic layers dried with Na₂SO₄ and evaporated to drynessunder reduced pressure to give 315 mg of the title compound, which wasused without further purification.

LCMS, method 1, rt: 0.89 min, MS ES+ m/z=363 (M+H)⁺.

Intermediate 5DF3-(5-Methyl-1,3-thiazol-2-yl)-5-{[(3S)-5-oxomorpholin-3-yl]methoxy}benzoicacid

To a mixture of Intermediate 4DF in MeOH was added an aqueous NaOHsolution (1.2 mL, 2.0 M, 2.4 mmol). The mixture was stirred at RT untilcomplete conversion. The pH value was adjusted to pH: 5, and thereaction mixture extracted with EtOAc. The combined organic layers weredried with Na₂SO₄, filtered off and evaporated to dryness under reducedpressure to give 330 mg (98% yield) of the title compound, which wasused without further purification.

LCMS, method 1, rt: 0.84 min, MS ES+ m/z=349 (M+H)⁺.

Intermediate 1723-{[5-(tert-Butoxycarbonyl)-2-oxa-5-azabicyclo[2.2.1]hept-1-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, as a mixture of two enantiomers

A mixture of Intermediate 4DG (630 mg, 1.37 mmol), aqueous NaOH solution(3.4 mL, 2.0 M, 6.8 mmol) and MeOH (20 mL) was stirred at RT untilcomplete conversion.

The MeOH was evaporated under reduced pressure. DCM and water were addedand the pH-value was adjusted to pH: 7 and the phases separated. Theaqueous layer was extracted twice with DCM and the combined organiclayers were evaporated to dryness to give 600 mg (98% yield) of thetitle compound, which was used without further purification.

¹H NMR (600 MHz, DMSO-d₆): δ [ppm] 1.36-1.49 (m, 9 H) 1.82-2.01 (m, 2 H)3.32-3.47 (m, 2 H) 3.71-3.80 (m, 1 H) 3.81-3.92 (m, 1 H) 4.36-4.55 (m, 3H) 7.54 (dd, 1 H) 7.65 (d, 2 H) 7.91-8.05 (m, 1 H) 12.94-13.73 (m, 1 H).

Intermediate 1753-[(5-Methyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, as a Mixture of Two Enantiomers

A mixture of Intermediate 173 (100 mg, 267 μmol), an aqueous NaOHsolution (670 μL, 2.0 M, 1.3 mmol) in MeOH (10 mL) was stirred at RTuntil complete conversion. The solvent was evaporated under reducedpressure, DCM and water were added and the pH-value was adjusted to pH:7. The aqueous layer was collected and evaporated to dryness to give 50mg (52% yield) of the title compound.

LCMS, method 1, rt: 0.68 min, MS ES+ m/z=361 (M+H)⁺.

Intermediate 1763-[(5-Isopropyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, as a Mixture of Two Enantiomers

A mixture of Intermediate 174 (150 mg, 373 μmol), an aqueous NaOHsolution (930 μL, 2.0 M, 1.9 mmol) in MeOH (10 mL) was stirred at RTuntil complete conversion. The solvent was evaporated under reducedpressure, DCM and water were added and the pH-value was adjusted to pH:7. The layers were separated and the aqueous layer was extracted twicewith DCM. The combined organic layers were evaporated to dryness and theresidue purified by column chromatography to give 70.0 mg (48% yield) ofthe title compound.

LCMS, method 1, rt: 0.73 min, MS ES+ m/z=389 (M+H)⁺.

Intermediate 114 Tert-butyl2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate,as a Mixture of Diastereoisomers

To a solution of Intermediate 5CF (497 mg, 0.995 mmol), Intermediate VI(228 mg, 1.19 mmol), DIPEA (693 μL, 3.98 mmol) in DCM (10 mL) was addedT3P (889 μL, 1.49 mmol, 50% solution in EtOAc) and the mixture stirredat RT for 2 h. The reaction mixture was washed with saturated NaHCO₃ (5mL). The organics were dried (MgSO₄), filtered and concentrated underreduced pressure. The crude material was purified by Biotage Isolera™chromatography (eluting with 30-80% EtOAc in heptane on a 25 gpre-packed KP-SiO₂ column) to give 520.4 mg (86% yield) of the titlecompound as colourless gum.

¹H NMR (500 MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.89 (t, J=1.4 Hz,1H), 7.56 (dd, J=2.3, 1.4 Hz, 1H), 7.53-7.51 (m, 1H), 7.40 (s, 1H),6.78-6.71 (m, 1H), 5.41-5.32 (m, 1H), 4.18-4.02 (m, 3H), 3.99-3.77 (m,3H), 3.65-3.55 (m, 1H), 3.13-2.73 (m, 2H), 2.53 (d, J=1.1 Hz, 3H), 1.71(d, J=7.2 Hz, 3H), 1.48 (s, 9H)

LC-MS (Method A) Rt=1.32 min, MS (ESIpos): m/z=608 (M+H)⁺.

In analogy to the procedure described for Intermediate 114, thefollowing Intermediates were prepared using T3P and the correspondingcarboxylic acid and primary amine starting materials.

Int. Structure Name Analytical Data 115

Tert-butyl 4- {[3-(5-methyl- 1,3-thiazol-2- yl)-5-({(1R)-1-[2-(trifluoro- methyl) pyrimidin-5- yl]ethyl} carbamoyl) phenoxy]methyl} piperidine-1- carboxylate ¹H NMR (500 MHz, chloroform-d): δ[ppm] 8.94 (s, 2H), 7.86 (s, 1H), 7.54-7.52 (m, 1H), 7.52-7.49 (m, 1H),7.38 (d, J = 1.6 Hz, 1H), 6.67 (d, J = 6.4 Hz, 1H), 5.36 (m, 1H), 3.90(d, J = 6.3 Hz, 2H), 2.82-2.71 (m, 2H), 2.54 (s, 3H), 2.03-1.93 (m, 1H),1.82 (d, J = 12.9 Hz, 2H), 1.72 (d, J = 7.2 Hz, 3H), 1.68-1.55 (m, 2H),1.47 (s, 9H), 1.36-1.23 (m, 2H). LC-MS (Method A) Rt = 1.42 min, MS(ESIpos): m/z = 550 (M-^(t)Bu)⁺. 117

Tert-butyl (2R)-2-{[3-(5- methyl-1,3- thiazol-2-yl)-5- ({[2-(trifluoro-methyl) pyrimidin-5- yl]methyl} carbamoyl) phenoxy] methyl} morpholine-4-carboxylate ¹H NMR (500 MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.93(s, 1H), 7.60-7.55 (m, 1H), 7.52 (d, J = 1.1, 1H), 7.44 (s, 1H), 7.02(s, 1H), 4.73 (d, J = 6.0, 2H), 4.10-4.04 (m, 2H), 4.01-3.76 (m, 4H),3.64-3.54 (m, 1H), 3.06-2.95 (m, 1H), 2.95- 2.76 (m, 1H), 2.53 (d, J =1.0, 3H), 1.48 (s, 9H). LC-MS (Method A) Rt = 1.35 min, MS (ESIpos): m/z= 594 (M + H)⁺. 119

Tert-butyl (2R)-2-{[3-(5- ethyl-1,3- thiazol-2-yl)-5- ({(lR)-1-[2-(trifluoro- methyl) pyrimidin-5- yl]ethyl} carbamoyl) phenoxy] methyl}morpholine- 4-carboxylate ¹H NMR (500 MHz, DMSO-d6): δ [ppm] 1.30 (t, J= 7.5 Hz, 3H), 1.42 (s, 9H), 1.62 (d, J = 7.1 Hz, 3H), 2.73-3.01 (m,4H), 3.47 (m, 1H), 3.70-3.78 (m, 2H), 3.83-3.99 (m, 2H), 4.12-4.23 (m,2H), 5.31 (m, 1H), 7.51-7.62 (m, 2H), 7.69 (s, 1H), 7.96 (s, 1H), 9.13(s, 2H), 9.16 (d, J = 7.1 Hz, 1H). LC-MS (Method A) Rt = 1.42 min, MS(ESIpos): m/z = 622 (M + H)⁺. 121

Tert-butyl (2S)-2-{[3-(5- ethyl-1,3- thiazol-2-yl)-5- ({(1R)-1[2-(trifluoro- methyl) pyrimidin-5- yl]ethyl} carbamoyl) phenoxy] methyl}morpholine- 4-carboxylate ¹H NMR (500 MHz, DMSO-d6): δ [ppm] 1.29 (t, J= 7.5 Hz, 3H), 1.41 (s, 9H), 1.61 (d, J = 7.1 Hz, 3H), 2.69-3.04 (m,4H), 3.42-3.50 (m, 1H), 3.68-3.77 (m, 2H), 3.83- 3.97 (m, 2H), 4.11-4.22(m, 2H), 5.30 (m, 1H), 7.54-7.59 (m, 2H), 7.66-7.69 (m, 1H), 7.95 (t, J= 1.4 Hz, 1H), 9.09-9.13 (m, 2H), 9.15 (d, J = 7.1 Hz, 1H). LC-MS(Method A) Rt = 1.46 min, MS (ESIpos): m/z = 622 (M + H)⁺ 125

Tert-butyl 3- fluoro-3-{[3- (5-methyl-1,3- thiazol-2-yl)-5- ({(1R)-1-[2-(trifluoro- methyl) pyrimidin-5- yl]ethyl} carbamoyl) phenoxy] methyl}azetidine-1- carboxylate ¹H NMR (500 MHz, DMS0-d6): δ [ppm] 1.40 (s,9H), 1.61 (d, J = 7.1 Hz, 3H), 2.51 (d, J = 1.0 Hz, 3H), 3.97-4.09 (m,2H), 4.15 (dd, J = 18.4, 10.3 Hz, 2H), 4.52 (d, J = 22.0 Hz, 2H), 5.30(m, 1H), 7.55- 7.60 (m, 1H), 7.60-7.63 (m, 1H), 7.65 (d, J = 1.2 Hz,1H), 7.96 (t, J = 1.4 Hz, 1H), 9.12 (s, 2H), 9.17 (d, J = 7.1 Hz, 1H).LC-MS (Method A) Rt = 1.35 min, MS (ESIpos): m/z = 596 (M + H)⁺. 119

Tert-butyl (2R)-2-{[3-(5- ethyl-1,3- thiazol-2-yl)- 5-({(1R)-1-[6-(trifluoro- methyl) pyridazin-3- yl]ethyl} carbamoyl) phenoxy] methyl}morpholine-4- carboxylate ¹H NMR (500 MHz, Chloroform-d): δ [ppm]7.93-7.90 (m, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H),7.63-7.60 (m, 1H), 7.57- 7.51 (m, 1H), 7.49-7.40 (m, 2H), 5.64-5.56 (m,1H), 4.19-3.77 (m, 6H), 3.66-3.56 (m, 1H), 3.07- 2.81 (m, 4H), 1.76 (d,J = 7.0 Hz, 3H), 1.48 (s, 9H), 1.36 (t, J = 7.5 Hz, 3H). LCMS (Method A)Rt = 1.42 min, MS (ESIpos): m/z = 622.15 (M + H)⁺. 121

Tert-butyl (2S)-2-{[3-(5- ethyl-1,3- thiazol-2-yl)- 5-({(1R)-1-[6-(trifluoro- methyl) pyridazin-3- yl]ethyl} carbamoyl) phenoxy] methyl}morpholine- 4-carboxylate ¹H NMR (500 MHz, Chloroform-d): δ [ppm]7.92-7.90 (m, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H),7.62-7.59 (m, 1H), 7.55- 7.53 (m, 1H), 7.49-7.41 (m, 2H), 5.66-5.52 (m,1H), 4.18-3.77 (m, 6H), 3.61 (td, J = 11.6, 2.4 Hz, 1H), 3.08-2.85 (m,4H), 1.76 (d, J = 7.0 Hz, 3H), 1.48 (s, 9H), 1.36 (t, J = 7.5 Hz, 3H).LCMS (Method A) Rt = 1.4 min, MS (ESIpos): m/z = 622.25 (M + H)⁺. 179

Tert-butyl (2S)-2-{[3-(5- methyl-1,3- thiazol-2-yl)-5- ({(1S)-1-[2-(trifluoro- methyl) pyrimidin-5- yl]ethyl} carbamoyl) phenoxy] methyl}morpholine- 4-carboxylate ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.90(s, 2H), 8.02-7.97 (m, 1H), 7.50-7.47 (m, 1H), 7.45 (d, J = 1.5 Hz, 1H),7.42-7.37 (m, 1H), 7.22 (s, 1H), 5.34-5.26 (m, 1H), 4.10-3.69 (m, 6H),3.56-3.48 (m, 1H), 2.97-2.71 (m, 2H), 2.47 (d, J = 1.0 Hz, 3H), 1.66 (d,J = 7.2 Hz, 3H), 1.41 (s, 9H). LCMS (Method A) Rt = 1.40 min, MS(ESIpos) m/z = 608 (M + H)⁺.

Intermediate 123 Tert-butyl(2S)-2-[[3-(5-chlorothiazol-2-yl)-5-[[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]carbamoyl]phenoxy]methyl]morpholine-4-carboxylate

To a solution of Intermediate 5CJ (150 mg, 0.31 mmol) and DIPEA (0.16mL, 0.94 mmol) in DCM (5 mL) was added Intermediate VI (86 mg, 0.38mmol) followed by HATU (121 mg, 0.94 mmol) and the reaction mixture wasstirred at ambient temperature for 2 h. The reaction mixture was washedwith water (5 mL), dried (MgSO₄), filtered and concentrated underreduced pressure to give crude residue that was purified by BiotageIsolera™ chromatography (eluting with 25-100% EtOAc in heptane on a 25 gpre-packed KP-SiO₂ column) to give 115 mg (56% yield) of the titlecompound as a solid.

¹H NMR (500 MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.83 (s, 1H), 7.67(s, 1H), 7.61-7.49 (m, 1H), 7.42 (s, 1H), 6.62 (s, 1H), 5.36 (m, 1H),4.20-4.01 (m, 3H), 4.00-3.83 (m, 2H), 3.86-3.74 (m, 1H), 3.60 (t, J=10.7Hz, 1H), 3.09-2.91 (m, 1H), 2.95-2.72 (m, 1H), 1.73 (d, J=7.1 Hz, 3H),1.48 (s, 9H).

LC-MS (Method A) Rt=1.47 min, MS (ESIpos): m/z=650 (M+H)⁺.

In analogy to the procedure described for Intermediate 123, thefollowing Intermediate was prepared using HATU and the correspondingcarboxylic acid and primary amine starting materials.

Int. Structure Name Analytical Data 177

Tert-butyl (2R)-2-[[3-(5- chlorothiazol- 2-yl)-5-[[(1R)- 1-[2-(trifluoro- methyl) pyrimidin-5- yl]ethyl] carbamoyl] phenoxy] methyl]morpholine- 4-carboxylate ¹H NMR (500 MHz, chloroform-d): δ [ppm] 8.94(s, 2H), 7.83 (t, J = 1.4 Hz, 1H), 7.67 (s, 1H), 7.57-7.49 (m, 1H), 7.42(s, 1H), 6.64 (s, 1H), 5.36 (m, 1H), 4.20-4.01 (m, 3H), 4.00-3.85 (m,2H), 3.85-3.74 (m, 1H), 3.60 (t, J = 11.2 Hz, 1H), 3.11- 2.93 (m, 1H),2.92-2.69 (m, 1H), 1.73 (d, J = 7.1 Hz, 3H), 1.48 (s, 9H). LC-MS (MethodA) Rt = 1.45 min, MS (ESIpos): m/z = 650 (M + H)⁺.

Intermediate 148 Tert-butyl3-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}azetidine-1-carboxylate

A mixture of Intermediate 5CV (90.0 mg, 223 μmol), Intermediate VI (53.2mg, 234 μmol), HATU (118 mg, 312 μmol) and DIPEA (150 μL, 890 μmol) inDMF (3 mL) was stirred at RT until complete conversion. The DMF wasevaporated under reduced pressure, water and DCM added, and the aqueouslayer was extracted with DCM. The combined organics were evaporated todryness. Crude material was purified by column chromatography (silicagel, hexane/EtOAc gradient) to give 90 mg (70% yield) of the titlecompound.

LCMS, method 1, rt: 1.39 min, MS ES+ m/z=578 (M+H)⁺.

Intermediate 1163-(5-Methyl-1,3-thiazol-2-yl)-5-(piperidin-4-ylmethoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of Intermediate 115 (206 mg, 0.34 mmol) dissolved in DCM(5 mL) was added TFA (0.26 mL, 3.4 mmol) and the reaction stirred at RTfor 16 h. The reaction mixture was neutralised with saturated NaHCO₃solution. The organic phase was separated and the aqueous phaseextracted with DCM (2×5 mL). The combined organic phases were dried(MgSO₄), filtered and concentrated at reduced pressure. The residue wasfreeze-dried from MeCN/water to give 173.6 mg (100% yield) of the titlecompound as white powder.

¹H NMR (500 MHz, chloroform-d): δ [ppm] 8.98 (s, 2H), 7.83 (s, 1H),7.55-7.44 (m, 2H), 7.38 (s, 1H), 5.47-5.31 (m, 1H), 3.99-3.81 (m, 2H),3.47 (s, 2H), 2.91 (m, 2H), 2.56-2.40 (m, 3H), 2.08-1.90 (m, 3H), 1.73(m, 5H).

LC-MS (Method A) Rt=0.94 min, MS (ESIpos): m/z=506 (M+H)⁺.

In analogy to the procedure described for Intermediate 116, thefollowing Intermediates were prepared using TFA and the correspondingN-Boc protected starting material.

Int. Structure Name Analytical Data 118

3-(5-Methyl- 1,3-thiazol-2- yl)-5-[(2R)- morpholin-2- ylmethoxy]-N-{[2-(trifluoro- methyl) pyrimidin-5- yl]methyl} benzamide LC-MS (MethodA) Rt = 1.01 min, MS (ESIpos): m/z = 494 (M + H)⁺. 120

3-(5-Ethyl-1,3- thiazol-2-yl)-5- [(2R)- morpholin-2- ylmethoxy]-N-{(1R)-1-[2- (trifluoro- methyl) pyrimidin-5- yl]ethyl} benzamide ¹HNMR (500 MHz, DMS0-d6): δ [ppm] 9.14 (d, J = 7.1 Hz, 1H), 9.12 (s, 2H),7.97-7.91 (m, 1H), 7.67 (s, 1H), 7.58-7.51 (m, 2H), 5.30 (m, 1H), 4.06(d, J = 5.1 Hz, 2H), 3.77-3.67 (m, 2H), 3.47 (td, J = 10.6, 3.7 Hz, 1H),2.97-2.83 (m, 3H), 2.73-2.62 (m, 2H), 2.58- 2.53 (m, 1H), 1.61 (d, J =7.1 Hz, 3H), 1.29 (t, J = 7.5 Hz, 3H). LC-MS (Method A) Rt = 1.1 min, MS(ESIpos): m/z =522 (M + H)⁺. 122

3-(5-Ethyl-1,3- thiazol-2-yl)-5- [(2S)- morpholin-2- ylmethoxy]-N-{(1R)-1-[2- (trifluoro- methyl) pyrimidin-5- yl]ethyl} benzamide ¹H NMR(500 MHz, DMSO-d6): δ [ppm] 1.29 (t, J = 7.5 Hz, 3H), 1.61 (d, J = 7.1Hz, 3H), 2.52-2.58 (m, 1H), 2.61-2.73 (m, 2H), 2.85- 2.95 (m, 3H),3.43-3.53 (m, 1H), 3.68-3.79 (m, 2H), 4.06 (d, J = 4.9 Hz, 2H), 5.30 (m,1H), 7.53- 7.56 (m, 2H), 7.64-7.69 (m, 1H), 7.93 (t, J = 1.4 Hz, 1H),9.08-9.18 (m, 3H). LC-MS (Method A) Rt = 1.07 min, MS (ESIpos): m/z =522 (M + H)⁺. 124

3-(5- Chlorothiazol- 2-yl)-5-[[(2S)- morpholin-2- yl]methoxy]-N-[(1R)-1-[2- (trifluoro- methyl) pyrimidin-5- yl]ethyl] benzamide ¹H NMR(500 MHz, chloroform-d): δ [ppm] 8.95 (s, 2H), 7.80 (s, 1H), 7.65 (s,1H), 7.57-7.45 (m, 1H), 7.46-7.35 (m, 1H), 6.80 (d, J = 6.5 Hz, 1H),5.37 (m, 1H), 4.10 (dd, J = 9.8, 5.6 Hz, 1H), 4.05- 3.90 (m, 3H), 3.77(td, J = 11.5, 3.5 Hz, 1H), 3.11 (d, J = 11.7 Hz, 1H), 3.05-2.91 (m,2H), 2.90- 2.77 (m, 1H), 1.73 (d, J = 7.1 Hz, 3H). LC-MS (Method A) Rt =1.07 min, MS (ESIpos): m/z = 528 (M + H)⁺. 178

3-(5- Chlorothiazol- 2-yl)-5-[[(2R)- morpholin-2- yl]methoxy]-N-[(1R)-1[2- (trifluoro- methyl) pyrimidin-5- yl]ethyl] benzamide ¹H NMR(500 MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.80 (s, 1H), 7.66 (s,1H), 7.58-7.50 (m, 1H), 7.46-7.37 (m, 1H), 6.69 (d, J = 6.5 Hz, 1H),5.36 (m, 1H), 4.09 (dd, J = 9.9, 6.0 Hz, 1H), 4.01 (dd, J = 9.9, 4.2 Hz,1H), 3.99-3.86 (m, 2H), 3.72 (td, J = 11.3, 2.9 Hz, 1H), 3.11-3.02 (m,1H), 3.01- 2.85 (m, 2H), 2.80 (dd, J = 12.0, 10.4 Hz, 1H), 1.72 (d, J =7.1 Hz, 3H). LC-MS (Method A) Rt = 1.08 min, MS (ESIpos): m/z = 528 (M +H)⁺.

Intermediate 126 [(3R)-4-Methylmorpholin-3-yl]methanol

To a solution of 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butylester (750 mg, 3.45 mmol) in anhydrous THF (16.5 mL) at 0° C. undernitrogen was added LiAlH₄ solution (2.4 M in THF, 8.6 mL). The reactionmixture was stirred for 20 minutes at 0° C. then warmed to RT andstirred for a further 2 h. The reaction mixture was cooled to 0° C. andquenched with dropwise addition of water (1 mL), 15% aqueous NaOH (1 mL)and water (3 mL). The inorganic by-products were removed by filtrationthrough Celite®. The filtrate was concentrated under reduced pressure togive 475 mg (71% yield) of the title compound as colourless oil, whichwas used without further purification.

¹H NMR (250 MHz, chloroform-d): δ [ppm] 3.87-3.73 (m, 3H), 3.64-3.51 (m,2H), 3.40 (dd, J=11.5, 1.7 Hz, 1H), 2.71 (dt, J=11.5, 1.9 Hz, 1H), 2.41(td, J=11.4, 3.4 Hz, 1H), 2.33 (s, 3H), 2.25-2.15 (m, 1H).

In analogy to the procedure described for Intermediate 126, thefollowing Intermediate was prepared using LiAlH₄ and the correspondingN-Boc protected starting material.

Int. Structure Name Analytical Data 127

[(3S)-4- Methyl- morpholin- 3-yl] methanol ¹H NMR (250 MHz,chloroform-d): δ [ppm] 3.80 (ddd, J = 12.1, 8.6, 3.9 Hz, 3H), 3.67-3.48(m, 2H), 3.40 (dd, J = 11.5, 1.7 Hz, 1H), 2.78- 2.65 (m, 1H), 2.41 (td,J = 11.5, 3.4 Hz, 1H), 2.32 (s, 3H), 2.28 2.12 (m, 1H).

Intermediate 130tert-Butyl-3-fluoro-3-(hydroxymethyl)piperidine-1-carboxylate, as amixture of enantiomers

To a 0° C. solution of 1-Boc-3-fluoropiperidine-3-carboxylic acid (750mg, 3.03 mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogenatmosphere was added borane (1M in THF, 9.1 mL, 9.10 mmol) dropwise andthe resulting reaction mixture warmed to RT and for stirred for 18 h.The reaction was quenched by careful addition of methanol and evaporatedat reduced pressure. The residue was dissolved in ethyl acetate andwashed with saturated sodium hydrogen carbonate solution. The organiclayer was dried (MgSO₄), filtered and concentrated at reduced pressure.Purification by Biotage Isolera™ chromatography (eluting with 0-60%EtOAc in heptane on a 25 g pre-packed KP-SiO₂ column) gave 650 mg (95%yield) of the title compound as pale yellow viscous oil, whichsolidified on standing.

¹H NMR (500 MHz, chloroform-d): δ [ppm] 4.00-2.86 (m, 6H), 1.95-1.85 (m,1H), 1.84-1.65 (m, 2H), 1.60-1.52 (m, 1H), 1.49 (s, 9H).

Intermediate 27CQ tert-Butyl(2R)-2-{[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}morpholine-4-carboxylate

To a stirred solution of Intermediate 112 (896 mg, 4.12 mmol) in dry DMF(7.5 mL) was added NaH 60% dispersion in mineral oil (172 mg, 4.30mmol). After the mixture was stirred for 15 min Intermediate 26 (750 mg,3.44 mmol) was added and the resulting mixture stirred at RT for 16 h.The reaction mixture was poured onto brine and extracted into EtOAc. Theorganic layer was washed with brine, dried (MgSO₄), filtered andconcentrated at reduced pressure to give a brown oil. The crude materialwas purified by Biotage Isolera™ chromatography (eluting with 5-60%EtOAc in heptane on a 50 g pre-packed KP-SiO₂ column) to give 870.9 mg(59% yield) of the title compound as a colourless gum.

¹H NMR (250 MHz, chloroform-d): δ [ppm] 7.75 (t, J=1.4 Hz, 1H),7.71-7.68 (m, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.19 (dd, J=2.5, 1.3 Hz, 1H),4.17-3.74 (m, 6H), 3.67-3.54 (m, 1H), 3.10-2.77 (m, 2H), 2.54 (d, J=1.1Hz, 3H), 1.48 (s, 9H).

LC-MS (Method A) Rt=1.33 min, MS (ESIpos): m/z=416 (M+H)⁺.

In analogy to the procedure described for Intermediate 27CQ, thefollowing Intermediates were prepared using NaH and the correspondingfluoro-benzonitrile and alcohol starting materials.

Int. Structure Name Analytical Data 27CM

3-{[(3R)-4- Methylmorpholin- 3-yl]methoxy}-5- (5-methyl-1,3- thiazol-2-yl)benzonitrile ¹H NMR (250 MHz, chloroform-d): δ [ppm] 7.73 (t, J = 1.3Hz, 1H), 7.71- 7.66 (m, 1H), 7.53 (d, J = 1.0 Hz, 1H), 7.16 (dd, J =2.4, 1.3 Hz, 1H), 4.17-4.01 (m, 2H), 3.92 (dd, J = 11.3, 3.2 Hz, 1H),3.83 (dt, J = 11.3, 3.1 Hz, 1H), 3.70 (m, 1H), 3.56 (m, 1H), 2.75 (m,1H), 2.68- 2.51 (m, 4H), 2.49-2.37 (m, 4H). 27CN

3-{[(3S)-4- Methylmorpholin- 3-yl]methoxy}-5- (5-methyl-1,3- thiazol-2-yl)benzonitrile ¹H NMR (250 MHz, chloroform-d): δ [ppm] 7.76 (t, J = 1.3Hz, 1H), 7.74- 7.69 (m, 1H), 7.56 (d, J = 1.1 Hz, 1H), 7.19 (dd, J =2.4, 1.3 Hz, 1H), 4.20-4.04 (m, 2H), 3.95 (dd, J = 11.3, 3.2 Hz, 1H),3.86 (dt, J = 11.2, 3.0 Hz, 1H), 3.73 (m, 1H), 3.59 (dd, J = 11.3, 9.2Hz, 1H), 2.78 (dt, J = 11.8, 2.7 Hz, 1H), 2.69-2.58 (m, 1H), 2.56 (d, J= 1.0 Hz, 3H), 2.52-2.40 (m, 4H). 27CO

Tert-butyl 3- {[3-cyano-5-(5- methyl-1,3- thiazol-2- yl)phenoxy]methyl}-3- fluoroazetidine- 1-carboxylate ¹H NMR (250 MHz,chloroform-d): δ [ppm] 7.77 (t, J = 1.3 Hz, 1H), 7.75- 7.71 (m, 1H),7.55 (d, J = 1.2 Hz, 1H), 7.20 (dd, J = 2.4, 1.3 Hz, 1H), 4.32 (d, J =19.2 Hz, 2H), 4.22- 4.08 (m, 4H), 2.54 (d, J = 1.0 Hz, 3H), 1.47 (s,9H). LC-MS (Method A) Rt = 1.34 min, MS (ESIpos): m/z = 404 (M + H)⁺.27CP

tert-Butyl-3- {[3-cyano-5-(5- methyl-1,3- thiazol-2- yl)phenoxy]methyl}-3- fluoropiperidine- 1-carboxylate, as a mixture of enantiomers¹H NMR (250 MHz, chloroform-d): δ [ppm] 7.78 (s, 1H), 7.75-7.71 (m, 1H),7.57 (d, J = 1.1 Hz, 1H), 7.22 (dd, J = 2.3, 1.3 Hz, 1H), 4.16 (s, 1H),4.09 (s, 1H), 3.97 (s, 1H), 3.87- 3.61 (m, 1H), 3.57-3.25 (m, 1H),3.26-3.06 (m, 1H), 2.57 (d, J = 0.9 Hz, 3H), 2.12-1.79 (m, 3H),1.70-1.60 (m, 1H), 1.48 (s, 9H). LC-MS (Method A) Rt = 1.48 min, MS(ESIpos): m/z = 432 (M + H)⁺. 27CR

tert-Butyl (2S)-2-{[3- cyano-5-(5- methyl-1,3- thiazol-2- yl)phenoxy]methyl} morpholine-4- carboxylate ¹H NMR (250 MHz, chloroform-d): δ[ppm] 7.75 (t, J = 1.3 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.53 (d, J =1.1 Hz, 1H), 7.18 (dd, J = 2.4, 1.3 Hz, 1H), 4.20-3.75 (m, 6H [+EtOAc]),3.60 (m, 2H), 3.10-2.76 (m, 1H [+DMF]), 2.53 (d, J = 1.0 Hz, 3H), 1.48(s, 9H). LC-MS (Method A) Rt = 1.34 min, MS (ESIpos) m/z = 416 (M + H)⁺.27CS

tert-Butyl (2R)-2-{[3- cyano-5-(5- methyl-1,3- thiazol-2- yl)phenoxy]methyl} pyrrolidine-1- carboxylate ¹H NMR (250 MHz, chloroform-d): δ[ppm] 7.75-7.64 (m, 2H), 7.53 (s, 1H), 7.18 (s, 1H), 4.01 (m, 3H +EtOAc), 3.53-3.28 (m, 2H), 2.53 (s, 3H), 2.03-1.81 (m, 4H), 1.47 (s,9H). 27CT

tert-Butyl (2S)-2-{[3- cyano-5-(5- methyl-1,3- thiazol-2- yl)phenoxy]methyl} pyrrolidine-1- carboxylate ¹H NMR (250 MHz, chloroform-d): δ[ppm] 7.75-7.65 (m, 2H), 7.56- 7.51 (m, 1H), 7.18 (s, 1H), 4.31- 3.82(m, 3H), 3.56-3.26 (m, 2H), 2.53 (d, J = 1.0 Hz, 3H), 2.04-1.79 (m, 4H),1.47 (s, 9H). 27CU

Tert-butyl 3- {[3-cyano-5-(5- methyl-1,3- thiazol-2- yl)phenoxy]methyl}-4,4- difluoropiperidine- 1-carboxylate, as a mixture ofenantiomers LC-MS (Method A) Rt = 1.45 min, MS (ESIpos): m/z = 450 (M +H)⁺.

Intermediate 5CE can also be synthesised from Intermediate 27CQ asillustrated below.

Intermediate 5CE3-{[(2R)-4-(Tert-butoxycarbonyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

A stirred solution of Intermediate 27CQ (0.87 g, 2.01 mmol), DMSO (10mL) and 2 M aqueous sodium hydroxide (10 mL) was heated at 110° C. for 3h. After cooling to RT the mixture was slowly acidified to pH ˜4,diluted with water (10 mL) and extracted with EtOAc (3×20 mL). Thecombined organics were washed with water (20 mL), brine (20 mL), dried(MgSO₄), filtered and concentrated under reduced pressure to give 672.1mg (77% yield) of the title compound as a foam.

¹H NMR (500 MHz, chloroform-d): δ [ppm] 8.29 (t, J=1.4 Hz, 1H), 7.70 (s,1H), 7.67 (dd, J=2.4, 1.3 Hz, 1H), 7.57 (d, J=1.1 Hz, 1H), 4.16 (dd,J=9.9, 5.5 Hz, 1H), 4.10 (dd, J=9.9, 4.5 Hz, 1H), 3.97 (d, J=10.7 Hz,1H), 3.94-3.80 (m, 2H), 3.66-3.57 (m, 1H), 3.10-2.97 (m, 1H), 2.90 (s,1H), 2.63 (s, 2H), 2.53 (d, J=1.0 Hz, 3H), 1.49 (s, 9H).

LC-MS (Method A) Rt=1.20 min, MS (ESIpos): m/z=435.55 (M+H)⁺.

Intermediate 28CM3-{[(3R)-4-Methylmorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid-chlorosodium (1:3)

To a solution of Intermediate 27CM (304 mg, 0.83 mmol) in ethanol (2 mL)was added 2 M aqueous sodium hydroxide (1.24 mL) and the resultantmixture heated to 120° C. by microwave irradiation for 30 min. Thecooled solution was diluted with water and washed with EtOAc. Theaqueous phase was separated, neutralised with 1 M HCl (0.88 mL) andconcentrated at reduced pressure. The residue was further dried in avacuum oven to constant weight to give 381 mg (88% yield) of the titlecompound, which was used without further purification.

LC-MS (Method A) Rt=0.80 min, MS (ESIpos) m/z=349 (M+H)⁺.

Intermediate 28CN3-{[(3S)-4-Methylmorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid hydrochloride (1:1)

To a stirred solution of Intermediate 27CN (200 mg, 0.53 mmol) in DMSO(3 mL) was added 2 M aqueous sodium hydroxide (3.5 mL) and the resultantmixture heated to 110° C. for 3 h. After cooling to RT the mixture wasslowly acidified to pH ˜2 with HCl and concentrated under reducedpressure to afford the crude material in DMSO. The residue waspartitioned between water and chloroform/isopropanol (1:1). The organiclayer was separated and the aqueous layer extracted twice withchloroform/isopropanol (1:1). The combined organic fraction was dried(magnesium sulfate), filtered and concentrated under reduced pressure.LC-MS (Method A) indicated product remained in the aqueous phase. Theorganic and aqueous layers were dried to remove residual DMSO, providing75 mg (36% yield) and 100 mg (49% yield, not corrected for sodiumchloride content). The combined fractions were used in the next stepwithout further purification.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 10.76 (s, 1H), 8.03 (s, 1H), 7.74 (s,1H), 7.72-7.57 (m, 2H), 7.61 (s, 1H), 4.52 (dd, J=11.1, 2.9 Hz, 1H),4.44 (dd, J=11.3, 2.8 Hz, 1H), 4.15 (d, J=10.2 Hz, 1H), 4.02 (d, J=12.3Hz, 1H), 3.86-3.79 (m, 1H), 3.78-3.68 (m, 2H), 3.29 (d, J=11.6 Hz, 1H),2.92 (d, J=3.1 Hz, 3H), 2.53 (s, 3H).

LC-MS (Method A) Rt=0.94 min, MS (ESIpos): m/z=349 (M+H)⁺.

Intermediate 28CP3-{[1-(Tert-butoxycarbonyl)-3-fluoropiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, as a mixture of enantiomers

To a stirred solution of Intermediate 27CP (400 mg, 0.83 mmol) inethanol (5 mL) was added 2M sodium hydroxide (1.25 mL, 2.50 mmol) andthe mixture heated to 80° C. for 18 h in a sealed tube. The reactionmixture was concentrated at reduced pressure and the aqueous residuewashed with ethyl acetate. The aqueous layer was acidified to pH 4 with2M HCl resulting in precipitation of white solid that was collected byfiltration and dried to give 310 mg (80% yield) of the title compound asan off-white solid.

LC-MS (Method A) Rt=1.26 min, MS (ESIpos): m/z=451.6 (M+H)⁺.

Intermediate 28CR3-{[(2S)-4-(Tert-butoxycarbonyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

A stirred solution of Intermediate 27CR (510 mg, 1.191 mmol) in EtOH (5mL) and 2M NaOH (1.79 mL) was heated to 130° C. for 3 hours undermicrowave irradiation. The reaction was quenched by addition of HCl (2M,1.79 mL) and concentrated under reduced pressure. The white residue wasslurried in chloroform and inorganic material removed by filtration. Thefiltrate was evaporated at reduced pressure to give 571 mg (79% yield)of the title compound as white powder.

¹H NMR (500 MHz, chloroform-d): δ [ppm] 8.29-8.25 (m, 1H), 7.68 (s, 2H),7.56 (d, 1H), 4.17-4.08 (m, 3H), 3.96 (d, J=11.1 Hz, 1H), 3.84 (br.s,2H), 3.73 (q, J=7.0 Hz, 1H), 3.65-3.58 (m, 2H), 2.52 (s, 3H), 1.48 (s,9H).

LC-MS (Method A) Rt=1.22 min, MS (ESIpos): m/z=434.95 (M+H)⁺.

Intermediate 28CS3-{[(2R)-1-(Tert-butoxycarbonyl)pyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

A stirred solution of Intermediate 27CS (0.348 g, 0.76 mmol) in ethanol(2 mL) and 2 M aqueous NaOH (1.0 mL, 2 mmol) was heated to 80° C. in asealed tube for 3 h. A further portion of 2M aqueous NaOH (1.0 mL, 2mmol) was added and the mixture heated to 80° C. in a sealed tube for 6h. The reaction mixture was concentrated at reduced pressure and theresidue taken up in water and acidifed to form a white precipitate thatwas collected by filtration to give 0.31 g (81% yield) of the titlecompound.

LC-MS (Method A) Rt=1.34 min, MS (ESIpos) m/z=419 (M+H)⁺.

Intermediate 28CT3-{[(2S)-1-(Tert-butoxycarbonyl)pyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

A stirred solution of Intermediate 27CT (0.318 g, 0.69 mmol) in ethanol(2 mL) and 2 M aqueous NaOH (1.0 mL, 2 mmol) was heated to 80° C. in asealed tube for 3 h. The reaction mixture was concentrated at reducedpressure and the residue taken up in water and acidifed to form a whiteprecipitate that was collected by filtration to give 0.11 g (35% yield)of the title compound.

LC-MS (Method A) Rt=1.33 min, MS (ESIpos): m/z=419 (M+H)⁺.

Intermediate 28CU3-{[1-(Tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid, as a mixture of enantiomers

A stirred solution of Intermediate 27CU (340 mg, 0.68 mmol) in ethanol(1 mL) and 2 M aqueous sodium hydroxide (1 mL, 2 mmol) was heated bymicrowave irradiation to 120° C. for 1 h. The reaction mixture wasacidified with conc. HCl to give a white precipitate that was extractedinto ethyl acetate. The organic phase was separated, dried (MgSO₄),filtered and concentrated under reduced pressure to give 199 mg (62%yield) of the title compound.

LC-MS (Method A) Rt=1.31, MS (ESIpos): m/z=469 (M+H)⁺.

Intermediate 1283-[(3-Fluoroazetidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a solution of Intermediate 27CO (330 mg, 0.8 mmol) in DCM (10 mL) wasadded TFA (4 mL) and the reaction stirred for 4 h at RT then neutralisedwith saturated aqueous sodium bicarbonate solution. The organic layerwas separated and the aqueous layer extracted with 1:1 IPA/CHCl₃ (2×20mL). The combined organics were dried (MgSO₄), filtered and concentratedunder reduced pressure to give 243.7 mg (95% yield) of the titlecompound as an off-white powder.

¹H NMR (250 MHz, Methanol-d4): δ [ppm] 7.85 (t, J=1.4 Hz, 1H), 7.83-7.79(m, 1H), 7.62-7.59 (m, 1H), 7.46 (dd, J=2.5, 1.3 Hz, 1H), 4.46 (d,J=19.2 Hz, 2H), 4.16-3.94 (m, 4H), 2.55 (d, J=1.1 Hz, 3H).

LC-MS (Method A) Rt=0.90 min, MS (ESIpos): m/z=304 (M+H)⁺.

Intermediate 1293-[(3-Fluoro-1-methylazetidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

Intermediate 128 (246 mg, 0.77 mmol), 37% formaldehyde solution in water(289 μL, 3.86 mmol) and acetic acid (5 μL) were combined in methanol (10mL) and sodium triacetoxyborohydride (491 mg, 2.82 mmol) was added. Theresulting solution was stirred at RT for 2 h before evaporating underreduced pressure. The residue was taken up in saturated NaHCO₃ (5 mL)and extracted with DCM (3×5 mL). The combined organic phase was dried(MgSO₄), filtered and concentrated under reduced pressure to give 222.6mg (83% yield) of the title compound as brown gum.

¹H NMR (500 MHz, chloroform-d): δ [ppm] 7.76 (t, J=1.4 Hz, 1H), 7.73(dd, J=2.4, 1.5 Hz, 1H), 7.55-7.53 (m, 1H), 7.21 (dd, J=2.5, 1.3 Hz,1H), 4.37 (d, J=23.0 Hz, 2H), 3.70-3.63 (m, 2H), 3.23 (dd, J=21.6, 9.5Hz, 2H), 2.54 (d, J=1.1 Hz, 3H), 2.45 (s, 3H).

LC-MS (Method A) Rt=0.86 min, MS (ESIpos): m/z=318 (M+H)⁺.

In analogy to the procedure described for Intermediate 28CM, thefollowing Intermediate was prepared using NaOH and the correspondingbenzonitrile starting material.

Int. Structure Name Analytical Data 28CO

3-[(3-Fluoro-1- methylazetidin- 3-yl)methoxy]-5- (5-methyl-1,3-thiazol-2-yl) benzoic acid - chlorosodium (1:3) ¹H NMR (250 MHz,DMSO-d6): δ [ppm] 8.02 (s, 1H), 7.66 (d, J = 1.3 Hz, 2H), 7.56 (s, 1H),4.46 (d, J = 24.0 Hz, 2H), 3.66 (dd, J = 13.4, 9.8 Hz, 2H), 3.31-3.20(m, 2H), 2.40 (s, 3H). LC-MS (Method A) Rt = 0.84 min, MS (ESIpos): m/z= 337 (M + H)⁺.

Intermediate 131tert-Butyl-3-fluoro-3-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}piperidine-1-carboxylate,as a mixture of diastereoisomers

To a stirred solution of Intermediate 28CP (150 mg, 0.33 mmol),Intermediate VI (91 mg, 0.40 mmol) and DIPEA (0.17 mL, 0.99 mmol) indichloromethane (4 mL) was added HATU (189 mg, 0.50 mmol) and thereaction mixture stirred for 2 h at RT. The reaction mixture was washedwith water (5 mL), dried (MgSO₄), filtered and concentrated at reducedpressure. Purification by Biotage Isolera™ chromatography (eluting with25-90% EtOAc in heptane on a 25 g pre-packed KP-SiO₂ column) gave 162 mg(74% yield) of the title compound as white solid.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 9.09 (s, 2H), 8.94 (d, J=7.1 Hz, 1H),8.01-7.84 (m, 1H), 7.67-7.57 (m, 2H), 7.57-7.53 (m, 1H), 5.33 (m, 1H),4.35-4.16 (m, 2H), 4.12-3.95 (m, 1H), 3.85-3.64 (m, 1H), 3.46-3.16 (m,1H), 1.94-1.87 (m, 1H), 1.81-1.49 (m, 6H), 1.40 (s, 9H).

LC-MS (Method A) Rt=1.44 min, MS (ESIpos) m/z=624 (M+H)⁺.

In analogy to the procedure described for Intermediate 131, thefollowing Intermediates were prepared using HATU and the correspondingcarboxylic acid and primary amine starting materials.

Int. Structure Name Analytical Data 137

tert-Butyl- (2R)-2-{[3-(5- methyl-1,3- thiazol-2-yl)-5- ({(1R)-1-[6-(trifluoromethyl) pyridin-3- yl]ethyl} carbamoyl) phenoxy] methyl}morpholine-4- carboxylate ¹H NMR (250 MHz, chloroform-d): δ [ppm] 8.80(d, J = 1.6 Hz, 1H), 7.95-7.84 (m, 2H), 7.69 (d, J = 8.1 Hz, 1H),7.61-7.57 (m, 1H), 7.54 (d, J = 1.0 Hz, 1H), 7.46-7.40 (m, 1H), 6.63 (d,J = 7.1 Hz, 1H), 5.40 (m, 1H), 4.30-3.76 (m, 6H), 3.75-3.39 (m, 1H),3.12-2.86 (m, 2H), 2.55 (s, 3H), 1.69 (d, J = 7.1 Hz, 3H), 1.50 (s, 9H).LC-MS (Method A) Rt = 1.40 min, MS (ESIpos): m/z = 607 (M + H)⁺. 141

tert-Butyl- (2S)-2-{[3-(5- methyl-1,3- thiazol-2-yl)-5- ({(1R)-1[6-(trifluoromethyl) pyridin-3- yl]ethyl} carbamoyl) phenoxy] methyl}morpholine-4- carboxylate ¹H NMR (500 MHz, chloroform-d): δ [ppm] 8.80(d, J = 1.3 Hz, 1H), 7.95-7.85 (m, 2H), 7.68 (d, J = 8.1 Hz, 1H), 7.58(s, 1H), 7.56- 7.51 (m, 1H), 7.42 (s, 1H), 6.71 (s, 1H), 5.40 (m, 1H),4.24-4.05 (m, 3H), 4.03-3.85 (m, 2H), 3.82 (ddd, J = 10.2, 7.6, 4.9 Hz,1H), 3.62 (m, 1H), 3.12-2.95 (m, 1H), 2.94-2.67 (m, 1H), 2.55 (s, 3H),1.69 (d, J = 7.1 Hz, 3H), 1.50 (s, 9H). LC-MS (Method A) Rt = 1.38 min,MS (ESIpos): m/z = 607 (M + H)⁺. 145

Tert-butyl (2S)-2-{[3-(5- methyl-1,3- thiazol-2-yl)-5- ({(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl} carbamoyl) phenoxy] methyl}pyrrolidine-1- carboxylate ¹H NMR (250 MHz, chloroform-d): δ [ppm] 8.97(s, 2H), 7.97 (s, 1H), 7.82 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H),7.40-7.32 (m, 1H), 5.53- 5.40 (m, 1H), 4.36-4.03 (m, 2H), 3.98-3.79 (m,1H), 3.54-3.17 (m, 2H), 2.50 (s, 3H), 2.07-1.87 (m, 4H), 1.71 (d, J =7.1 Hz, 3H), 1.40 (s, 9H). 143

Tert-butyl (2R)-2-{[3-(5- methyl-1,3- thiazol-2-yl)-5- ({(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl} carbamoyl) phenoxy] methyl}pyrrolidine-1- carboxylate ¹H NMR (250 MHz, chloroform-d): δ [ppm] 8.95(s, 2H), 8.04-7.96 (m, 1H), 7.95-7.85 (m, 1H), 7.65 (s, 1H), 7.50 (s,1H), 7.44-7.32 (m, 1H), 5.60-5.39 (m, 1H), 4.42- 4.27 (m, 1H), 4.26-4.12(m, 1H), 3.95-3.82 (m, 1H), 3.50-3.36 (m, 1H), 3.35-3.19 (m, 1H), 2.52(s, 3H), 2.07-1.87 (m, 4H), 1.76 (d, J = 7.0 Hz, 3H), 1.42 (s, 9H).

Intermediate 139 Tert-butyl(2R)-2-{[3-({(1R)-1-[6-(difluoromethyl)pyridin-3-yl]ethyl}carbamoyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}morpholine-4-carboxylate

To a stirred solution of Intermediate 5CE (80 mg, 0.18 mmol),Intermediate LIV (46 mg, 0.17 mmol) and DIPEA (0.15 mL, 0.88 mmol) inDCM (2 mL) was added T3P (50% solution in EtOAc, 0.21 mL, 0.35 mmol).The reaction mixture was stirred at RT for 2 h then washed withsaturated sodium bicarbonate solution (3 mL). The aqueous phase wasre-extracted with DCM (3 mL) and the combined organics passed through aphase separator and concentrated under reduced pressure. The crudematerial was purified by Biotage Isolera™ chromatography (eluting with0-2% MeOH in DCM on a 25 g pre-packed KP-SiO₂ column) to give 58 mg (53%yield) of the title compound as a colourless gum.

¹H NMR (500 MHz, chloroform-d): δ [ppm] 8.71 (d, J=1.7 Hz, 1H), 7.89 (s,1H), 7.86 (dd, J=8.1, 2.2 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.58-7.54 (m,1H), 7.53-7.51 (m, 1H), 7.42 (s, 1H), 6.81-6.46 (m, 2H), 5.46-5.32 (m,1H), 4.22-3.75 (m, 6H), 3.69-3.51 (m, 1H), 3.07-2.78 (m, 2H), 2.53 (d,J=1.0 Hz, 3H), 1.66 (d, J=7.1 Hz, 3H), 1.48 (s, 9H).

LC-MS (Method A) Rt=1.32 min, MS (ESIpos): m/z=589 (M+H)⁺.

In analogy to the procedure described for Intermediate 139, thefollowing Intermediate was prepared using T3P and the correspondingcarboxylic acid and primary amine starting materials.

Int. Structure Name Analytical Data 146

Tert-butyl-4,4- difluoro-3-{[3- (5-methyl-1,3- thiazol-2-yl)-5-({(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} carbamoyl)phenoxy] methyl} piperidine-1- carboxylate, as a mixture ofdiastereoisomers ¹H NMR (250 MHz, chloroform-d): δ [ppm] 8.95 (s, 2H),7.88 (s, 1H), 7.58-7.47 (m, 2H), 7.37 (s, 1H), 6.92 (s, 1H), 5.36 (q, J= 6.9 Hz, 1H), 4.43-3.81 (m, 4H), 3.41 2.88 (m, 2H), 2.53 (d, J = 0.9Hz, 3H), 2.50-2.31 (m, 1H), 2.13- 1.80 (m, 2H), 1.73 (d, J = 7.1 Hz,3H), 1.43 (s, 9H). LC-MS (Method A) Rt = 1.43 min, MS (ESIpos): m/z =642 (M + H)⁺.

Intermediate 1383-(5-Methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

To a solution of Intermediate 137 (126 mg, 0.18 mmol) in dichloromethane(5 mL) was added trifluoroacetic acid (0.28 mL, 3.66 mmol) and thereaction mixture stirred at ambient temperature for 16 h. The reactionmixture was passed through an SCX cartridge (washing with methanol andeluting with 7N ammonia in methanol) to give 85 mg (92% yield) of thetitle compound as a glass solid.

¹H NMR (250 MHz, chloroform-d): δ [ppm] 8.80 (d, J=1.6 Hz, 1H),7.97-7.82 (m, 2H), 7.68 (d, J=8.1 Hz, 1H), 7.61-7.55 (m, 1H), 7.53 (d,1H), 7.49-7.36 (m, 1H), 6.68 (d, J=6.9 Hz, 1H), 5.40 (m, 1H), 4.21-3.82(m, 4H), 3.73 (td, J=11.0, 3.5 Hz, 1H), 3.15-2.64 (m, 4H), 2.55 (s, 3H),1.69 (d, J=7.1 Hz, 3H).

LC-MS (Method A) Rt=0.96 min, MS (ESIpos): m/z=507 (M+H)⁺.

In analogy to the procedure described for Intermediate 138, thefollowing Intermediates were prepared using TFA and the correspondingN-Boc protected starting materials.

Int. Structure Name Analytical Data 142

3-(5-Methyl- 1,3-thiazol-2- yl)-5-[(2S)- morpholin-2- ylmethoxy]-N-{(1R)-1-[6- (trifluoromethyl) pyridin-3- yl]ethyl} benzamide ¹H NMR (500MHz, chloroform-d): δ [ppm] 8.81 (s, 1H), 7.95-7.80 (m, 2H), 7.68 (d, J= 8.1 Hz, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 7.43 (s, 1H), 6.69 (d, J =6.2 Hz, 1H), 5.40 (m, 1H), 4.10 (dd, J = 9.9, 5.9 Hz, 1H), 4.05 (dd, J =9.9, 4.2 Hz, 1H), 4.01- 3.87 (m, 2H), 3.74 (td, J = 11.3, 2.7 Hz, 1H),3.07 (d, J = 11.7 Hz, 1H), 3.00-2.86 (m, 2H), 2.86- 2.74 (m, 1H), 2.55(s, 3H), 1.69 (d, J = 7.1 Hz, 3H). LC-MS (Method A) Rt = 0.99 min, MS(ESIpos): m/z = 507 (M + H)⁺. 132

3-(Fluoro- piperidin-3-yl) methoxy}-5- (5-methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide, as amixture of 2 diastereoisomers ¹H NMR (500 MHz, chloroform-d): δ [ppm]8.95 (d, J = 1.1 Hz, 2H), 7.85 (s, 1H), 7.53 (s, 1H), 7.50 (s, 1H), 7.41(d, J = 5.3 Hz, 1H), 6.99 (s, 1H), 5.36 (m, 1H), 4.19-3.94 (m, 2H),3.33-3.17 (m, 1H), 3.06- 3.00 (m, 1H), 2.90 (m, 1H), 2.68 (t, J = 10.9Hz, 1H), 2.52 (s, 3H), 2.09- 1.98 (m, 1H), 1.88-1.75 (m, 2H), 1.71 (d, J= 7.1 Hz, 3H), 1.65-1.52 (m, 1H). LC-MS (Analytical Method F) Rt = 2.17min, MS (ESIpos): m/z = 524 (M + H)⁺. 140

N-{(1R)-1-[6- (Difluoromethyl) pyridin-3- yl]ethyl}-3-(5- methyl-1,3-thiazol-2-yl)-5- [(2R)- morpholin-2- ylmethoxy] benzamide ¹H NMR (500MHz, chloroform-d): δ [ppm] 8.75-8.67 (m, 1H), 7.88- 7.83 (m, 2H), 7.62(d, J = 8.1 Hz, 1H), 7.58-7.54 (m, 1H), 7.52- 7.49 (m, 1H), 7.44-7.39(m, 1H), 6.77-6.49 (m, 2H), 5.38 (m, 1H), 4.16-3.90 (m, 4H), 3.74 (td, J= 11.2, 3.2 Hz, 1H), 3.08 (d, J = 12.1 Hz, 1H), 3.03-2.68 (m, 3H), 2.52(s, 3H), 1.66 (d, J = 7.1 Hz, 3H). LC-MS (Method A) Rt = 0.96 min, MS(ESIpos): m/z = 489 (M + H)⁺. 144

3-(5-Methyl- 1,3-thiazol-2- yl)-5-[(2R)- pyrrolidin-2- ylmethoxy]-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide LC-MS(Method A) Rt = 0.94 min, MS (ESIpos): m/z = 492 (M + H)⁺.

Intermediate 1333-(5-Methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]benzoic acidtrifluoroacetate (1:1)

To a solution of Intermediate 5CE (120 mg, 0.276 mmol) in DCM was addedtrifluoroacetic acid (2 mL, 25.96 mmol) and the reaction stirred at RTfor 1 hour. The reaction was stopped and concentrated under reducedpressure to give 200 mg (quantitative yield; residual TFA present) ofthe title compound as pale yellow oil.

LC-MS (Method A) Rt=0.85 min, MS (ESIpos): M/Z=335 [M+H]⁺.

Intermediate 1343-{[(2R)-4-Methylmorpholin-2-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid

To a solution of Intermediate 133 (200 mg, 0.45 mmol), formaldehyde (37%in water, 167.1 μL, 2.23 mmol) and acetic acid (38.3 μL, 1.05 mmol) inMeOH (2 mL) was added STAB (283.6 mg, 1.34 mmol) and mixture stirred atRT for 1 hour. The solvent was evaporated and the resulting residuebasified to pH 8-9 using saturated NaHCO₃ and extracted in DCM (3×5 mL).The aqueous layer was neutralised to pH 7 with acid and concentratedunder reduced pressure to give the title compound 859 mg (quantitativeyield; inorganic salts present).

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 7.92-7.91 (m, 1H), 7.57 (d, J=1.1 Hz,1H), 7.47 (dd, 1H), 7.36-7.34 (m, 1H), 4.03-4.00 (m, 2H), 3.83-3.77 (m,3H), 3.55 (td, J=11.2, 8.8 Hz, 3H), 2.81-2.77 (m, 1H), 2.62-2.58 (m,1H), 2.20 (s, 3H), 2.00 (td, 1H), 1.90 (t, J=10.7 Hz, 1H).

LC-MS (Method A) Rt=0.93 min, MS (ESIpos): m/z=349 (M+H)⁺.

Intermediate 1473-{[3-Fluoro-1-methylpiperidin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,as a mixture of 2 diastereoisomers

To a solution of Intermediate 132 (55 mg, 0.1 mmol) in methanol (1 mL)was added formaldehyde (37% in water, 16 uL, 0.21 mmol) and acetic acid(6 uL, 0.1 mmol) and the reaction stirred for 15 minutes at RT. STAB (33mg, 0.16 mmol) was added and the reaction stirred for 1 h at RT. Thereaction mixture was passed through an SCX cartridge (washing withmethanol, eluting with 7N ammonia in methanol) and concentrated underreduced pressure to give 52 mg (91% yield) of the title compound as anoff-white glass.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.17 (d, J=7.0 Hz, 1H), 9.12 (s, 2H),7.93 (s, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 5.30 (m, 1H),4.27 (d, J=22.1 Hz, 2H), 2.62-2.53 (m, 2H), 2.39-2.31 (m, 1H), 2.29-2.22(m, 1H), 2.19 (s, 3H), 1.87-1.77 (m, 1H), 1.75-1.67 (m, 2H), 1.61 (d,J=7.1 Hz, 3H), 1.58-1.48 (m, 1H).

LC-MS (Analytical Method F) Rt=2.19 min, MS (ESIpos): m/z=538 (M+H)⁺.

Intermediate I Ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate

Note: The reaction was split into two 37.5 g batches, and the isolatedproduct combined into one batch.

To a solution of ethyl4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (37.5 g, 142.9mmol) in ethanol (750 mL) was added DIPEA (68 mL, 392.3 mmol), 10% Pd/C(50% wet, 3 g) and the reaction mixture stirred under an atmosphere ofhydrogen for 1 h. The reaction mixture was filtered through glass fibrefilter paper and the filtrate concentrated under reduced pressure togive a yellow solid. The solid was taken up in EtOAc (500 mL), washedwith water (500 mL), 1M aq HCl (500 mL), saturated aq. NaHCO₃ (500 mL),dried (over MgSO₄), filtered and concentrated under reduced pressure.The pale yellow solid was triturated with heptane and the solidcollected by filtration. The filtrate was concentrated and triturationrepeated with heptane. The mother liquers from both batches werecombined and purified by Biotage Isolera™ chromatography (eluting with1-30% EtOAc in heptane on a 100 g KP-SiO₂ column). The productcontaining fractions were concentrated and the residue triturated withheptane. All the solids were combined to give 56.8 g (90% yield) of thetitle compound as yellow solid.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 9.43 (s, 2H), 4.50 (q, J=7.1 Hz,2H), 1.45 (t, J=7.1 Hz, 3H).

LCMS (Analytical Method A) Rt=1.24 min, MS (ESIpos): m/z=220.9 (M+H)⁺.

Intermediate II 2-(Trifluoromethyl)pyrimidine-5-carboxylic acid

To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate (56.8g, 252.8 mmol) dissolved in THF (500 mL) was added 1M aq. LiOH (380 mL,379.3 mmol). The reaction mixture was stirred at RT for 16 h,concentrated under vacuum to remove the organic solvent and theremaining aqueous acidified to pH 1 with conc. HCl. The resultantprecipitate was collected by vacuum filtration to afford 44.4 g (91%yield) of the title compound as off-white powder.

¹H NMR (500 MHz, DMSO-d₆): δ [ppm] 9.44 (s, 2H).

LCMS (Analytical Method A) Rt=0.81 min, MS (ESIneg): m/z=190.9 (M)−.

Intermediate IIIN-Methoxy-N-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamide

2-(Trifluoromethyl)pyrimidine-5-carboxylic acid (44.39 g, 231.1 mmol),methoxymethanine hydrochloride (33.8 g, 346.6 mmol) and DIPEA (119.5 mL,924.3 mmol) were combined in DCM (750 mL) then HATU (105.4 g, 277.3mmol) was added and the mixture stirred at RT for 2 h. The reactionmixture was washed with water (3×300 mL), the organic phase collected,dried (over MgSO₄), filtered and concentrated in vacuo to give a viscousyellow oil. The crude material was purified by dry flash chromatography(eluting with 0-40% EtOAc in heptane) to give 54.2 g (95% yield) of thetitle compound as a free flowing pale yellow oil.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 9.22 (s, 2H), 3.61 (s, 3H), 3.43(s, 3H).

LCMS (Analytical Method A) Rt=1.03 min, MS (ESIpos): m/z=235.9 (M+H)⁺.

Intermediate IV 1-[2-(Trifluoromethyl)pyrimidin-5-yl]ethanone

N-Methoxy-N-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamide (54.9 g,218.9 mmol) was dissolved in dry THF (550 mL) and cooled to 0° C. in anice bath. Methyl magnesium bromide (1.4M in toluene/THF, 188 mL, 262.7mmol) was added dropwise over 30 minutes. The reaction was stirred for afurther 10 min at 0° C., quenched slowly with 1M HCl (260 mL) andstirred for another 30 mins before extracting with ethyl acetate (300mL). The organic phase was separated, dried (over MgSO₄), filtered andconcentrated in vacuo to give a yellow solid. LCMS and ¹H NMR showedpresence of ˜20 mol % of unhydrolysed intermediate, hence the solid wasstirred in a mixture of 2M HCl (200 mL) and DCM (200 mL) for 20 min. Thelayers were separated and the aqueous layer extracted with further DCM(2×100 mL). The combined organics were dried (over MgSO₄), filtered andconcentrated under reduced pressure to afford 33.57 g (80% yield) of thetitle compound as yellow solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 9.36 (s, 2H), 2.72 (s, 3H).

LCMS (Analytical Method A) Rt=0.99 min, MS (ESIpos): m/z=191.0 (M+H)⁺.

Intermediate V(S)-2-Methyl-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}propane-2-sulfinamide

To a stirred solution of 1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanone(20.65 g, 107.5 mmol) and titanium(IV) ethoxide (69.4 mL, 215.1 mmol) inEt₂O (1 L) was added (S)-2-t-butylsulfinamide (14.3 g, 118.3 mmol) andthe resulting solution stirred at reflux overnight under nitrogenatmosphere. The reaction mixture was cooled to −78° C. and L-selectride(118.3 mL, 1M sol. in THF) added dropwise maintaining an internaltemperature below −70° C. The reaction was stirred at −78° C. for afurther 2 h, after which time LCMS (Analytical Method A) showed residualimine intermediate. The reaction mixture was re-treated withL-selectride (12 mL, 1M sol. in THF) and stirred for 1 h. LCMS showedcomplete conversion of imine. The reaction was quenched by addition ofbrine (500 mL) and warmed to RT. The suspension was filtered through aplug of celite, washing with EtOAc. The filtrate was washed with brine(500 mL), and the aqueous layer re-extracted with EtOAc (2×300 mL). Thecombined organics were dried (over MgSO₄), filtered and concentratedunder reduced pressure. The residue was triturated with Et₂O and theresulting precipitate collected by vacuum filtration to give 18.12 g(57% yield) of the title compound as off-white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.88 (s, 2H), 4.75 (qd, J=6.8,3.1 Hz, 1H), 3.43 (d, J=2.5 Hz, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.24 (s,9H).

LCMS (Analytical Method A) Rt=1.14 min, MS (ESIpos): m/z=296.0 (M+H)⁺.

Intermediate VI (1R)-1-[2-(Trifluoromethyl)pyrimidin-5-yl]ethan-1-aminehydrochloride (1:1)

To a solution of(S)-2-methyl-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]propane-2-sulfinamide(14.37 g, 48.66 mmol) dissolved in methanol (140 mL) was added 4M HCl indioxane (120 mL) and the resulting solution stirred for 1 h at RT. Thereaction mixture was concentrated in vacuo, diethyl ether added toprecipitate the title compound 10.06 g (91% yield) as an off-white solidafter collection by vacuum filtration.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 9.28 (s, 2H), 8.96 (s, 2H), 4.67 (q,J=6.9 Hz, 1H), 1.64 (d, J=6.9 Hz, 3H).

Analytical HPLC: Column: Chiralpak AD-H 25 cm; Mobile phase: 90:10Heptane: Ethanol; Flow rate: 0.3 ml/min; Detection: UV 254 nm; Runtime:70 mins; Rt=49.44 min; 100% ee.

Intermediate VII(S)-2-Methyl-N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]propane-2-sulfinamide

1-(6-Methylpyridin-3-yl)ethan-1-one (1.6 g, 11.8 mmol) and(S)-tert-butylsulfinamide (1.4 g, 11.8 mmol) were dissolved in THF (20mL). Titanium(IV) ethoxide (containing 33% TiO₂) (6.1 g, 17.8 mmol) wasadded and the reaction mixture stirred at 80° C. for 2 hours. Thereaction mixture was cooled to −78° C. and L-Selectride (1M soln in THF,11.8 mL, 11.8 mmol) was added dropwise over 30 mins, maintaining ininternal reaction temperature below −70° C. The reaction mixture wasstirred at −78° C. for 1 hour and then quenched with MeOH (2 mL). Thesolution was allowed to warm to RT and diluted with water (50 mL). Theresulting solid was removed via vacuum filtration, the filtratecollected and solvent removed in vacuo. The residue was taken up inbrine (40 mL) and extracted with TBME (2×60 mL). The combined organicswere dried (over Na₂SO₄), filtered and concentrated under reducedpressure. The crude material was purified by Biotage Isolera™chromatography (eluting with 0-20% MeOH in DCM) to give 1.25 g (34%yield) of the title compound.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.46 (d, J=2.2, 1H), 7.53 (dd,J=8.0, 2.3, 1H), 7.13 (d, J=8.0, 1H), 4.57 (qd, J=6.7, 6.7, 6.7, 3.4,1H), 2.55 (s, 3H), 1.54 (d, J=6.7, 3H), 1.18 (s, 9H).

Intermediate VIII (1R)-1-(6-Methylpyridin-3-yl)ethanamine hydrochloride

To a solution of(S)-2-methyl-N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]propane-2-sulfinamide(1.25 g, 4.1 mmol) in 2-propanol (5 mL) cooled to 0° C. in an ice bathwas added 5M HCl in 2-propanol (4 mL, 20 mmol). The mixture was allowedto warm to RT and stirred for 1 hour. Formation of a white precipitatewas observed. The precipitate was collected by filtration and washedwith TBME to give 616 mg (78% yield) of the title compound as a whitesolid.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 8.98 (s, 3H), 8.85 (d, J=2.0 Hz, 1H),8.47 (dd, J=8.3, 2.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.53-7.24 (m, 2H),4.60 (s, 1H), 2.68 (s, 3H), 1.58 (d, J=6.9 Hz, 3H).

Intermediate IX 1-(5-Methylpyrazin-2-yl)ethanone

5-Methylpyrazine-2-carbonitrile (25.0 g, 210 mmol) was dissolved indiethyl ether (500 mL) and cooled to −15° C. To this was added methylmagnesium iodide (3M in THF, 84 mL, 241 mmol) dropwise over 1 hour andthe internal temperature maintained below −10° C. A cloudy orangeprecipitate formed during reactant addition. The reaction was quenchedby slowly pouring the mixture into 1M aq. HCl (250 mL) and crushed ice.The mixture was warmed to RT and basified with sat. aq, NaHCO₃. TBME(300 mL) was added and the organic layer collected. The aqueous layerwas extracted with TBME (2×300 mL) and the combined organic layers werewashed with brine (300 mL), dried (over Na₂SO₄), filtered andconcentrated under reduced pressure to give 18.4 g (61% yield) of thetitle compound as a yellow solid.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 8.97 (d, J=1.2 Hz, 1H), 8.68 (s, 1H),2.62 (s, 3H), 2.60 (s, 3H).

Intermediate X(S)-2-Methyl-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]propane-2-sulfinamide

1-(5-Methylpyrazin-2-yl)ethanone (27.2 g, 200 mmol),(S)-tert-butylsulfinamide (24.24 g, 200 mmol) and titanium(IV) ethoxide(102 g, 300 mmol; containing 33% TiO₂) were heated in THF (1000 mL) at80° C. for 1 hour then cooled to RT. TLC (EtOAc/acetone 1:1) indicatedconsumption of Intermediate IX. The mixture was cooled to −78° C. andL-Selectride (1 m in THF, 200 mL, 200 mmol) added dropwise over 60minutes with the internal temperature maintained below −70° C. Themixture was stirred at −78° C. for 1 hour then quenched by dropwiseaddition of MeOH (50 mL) and warmed to RT. Upon addition of water (100mL) a white precipitate formed that was collected by filtration andwashed with TBME (2 L). The aqueous layer of the filtrate was separatedand washed with TBME (2×200 mL). The combined organics were washed withbrine (100 mL), dried (over Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by dry flash chromatography(silica gel, eluting with 0-60% acetone in EtOAc) to give 35.8 g (49%yield) of the title compound as a brown oil.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 8.57 (d, J=1.1 Hz, 1H), 8.45 (s, 1H),5.56 (d, J=6.4 Hz, 1H), 5.29 (s, 1H), 4.56-4.44 (m, 1H), 2.47 (s, 3H),1.51 (d, J=6.9 Hz, 3H), 1.11 (s, 9H), 1.08 (s, 5H).

Intermediate XI (1R)-1-(5-Methylpyrazin-2-yl)ethanamine dihydrochloride

To a solution of(S)-2-methyl-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]propane-2-sulfinamide(35 g, 63.7 mmol) in 2-propanol (200 mL) was added 5M HCl in 2-propanol(65 mL, 325 mmol) at 0° C. The mixture was warmed to RT, resulting information of a precipitate. After stirring for 1 hour the precipitatewas collected by filtration. Recrystallisation from hot TBME (200 mL)gave 19.8 g (78% yield) of the title compound as a light brown solid.

¹H NMR (500 MHz, DMSO-d6) δ[ppm]: 8.70 (s, 4H), 8.59 (s, 1H), 4.57 (dq,J=12.2, 6.1 Hz, 1H), 2.52 (s, 3H), 1.53 (d, J=6.8 Hz, 3H).

Intermediate XII 6-Methylpyridazine-3-carbonitrile

A solution of 3-chloro-6-methylpyridazine (50 g, 389 mmol) in DMA (1250mL) was degassed under nitrogen for 10 minutes then zinc (II) cyanide(27.4 g, 233 mmol), zinc dust (1017 mg, 15.6 mmol) and Pd(dppf)Cl₂.DCM(12.7 g, 15.6 mmol) were added. The mixture was heated at 120° C.overnight. The reaction mixture was cooled to RT, diluted with DCM (1 L)and filtered through celite, washing with further DCM. The filtrate wasconcentrated under reduced pressure. The residue was purified by dryflash silica chromatography (eluting with TBME) to give 34.9 g (75%yield) of the title compound as an off-white solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.72 (d, J=8.6 Hz, 1H), 7.48 (d,J=8.6 Hz, 1H), 2.85 (s, 3H).

Intermediate XIII 1-(6-Methylpyridazin-3-yl)ethan-1-one

A solution of 6-methylpyridazine-3-carbonitrile (23.8 g, 200 mmol) inTBME (1.2 L) was stirred under nitrogen and cooled to −15° C. Methylmagnesium iodide (3M in Et₂O, 80 mL, 240 mmol) was added over ˜20 min,keeping the internal temperature below −15° C. The reaction mixture wasstirred for 1.5 h before quench by addition of 2M HCl (120 mL). Themixture was warmed to RT, the organic layer collected, dried (overNa₂SO₄), filtered and concentrated under reduced pressure to give ayellow solid. The aqueous layer was basified to pH 8-9 with NaHCO₃,extracted with DCM (4×200 mL) and the combined organics dried (overNa₂SO₄), filtered and concentrated under reduced pressure. The twobatches were combined to give 26.2 g (67% yield) of the title compoundas a yellow solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.02 (d, J=8.6 Hz, 1H), 7.46 (d,J=8.6 Hz, 1H), 2.87 (s, 3H), 2.81 (s, 3H).

Intermediate XIV(S)-2-Methyl-N-[(1R)-1-[6-methylpyridazin-3-yl)ethyl]propane-2-sulfinamide

To a stirred solution of 1-(6-methylpyridazin-3-yl)ethan-1-one (26.2 gcrude, 19.90 g purity corrected mass, 146.2 mmol) and titanium(IV)ethoxide (61.3 mL, 292.3 mmol) in dry THF (600 mL) was added(S)-2-t-butylsulfinamide (17.71 g, 146.2 mmol) and the resultingsolution stirred at 80° C. for 60 min. The solution was cooled to −70°C. and L-Selectride (1M in THF, 146.2 mL, 142 mmol) added dropwise,whilst maintaining an internal temperature below −72° C. The reactionmixture was stirred at −78° C. for 30 min, quenched by slow addition ofmethanol (30 mL) and allowed to warm to room temperature. Ethyl acetate(800 mL) and water (800 mL) were added resulting in precipitation. Thesolid was collected by filtration, washed with ethyl acetate (3×400 mL).Each 3×˜400 mL EtOAc filtrate was used to back-extract the aqueouslayer. The combined organics were dried (over Na₂SO₄), filtered andconcentrated under reduced pressure. The crude material waspart-purified by dry flash silica chromatography (eluting with EtOAcfollowed by acetone). Re-purification by dry flash silica chromatography(eluting with 50% acetone in EtOAc) gave 21.4 g (44% yield) of the titlecompound as a brown viscous oil.

¹H NMR (250 MHz, Chloroform-d): δ 7.40 [ppm] (d, J=8.6 Hz, 1H), 7.30 (d,J=8.6 Hz, 1H), 4.84 (p, J=6.7 Hz, 1H), 3.97 (d, J=6.1 Hz, 1H), 3.71 (s,1.3H), 2.70 (s, 3H), 1.68 (d, J=6.8 Hz, 3H), 1.22 (s, 6H), 1.20 (s, 9H).

Intermediate XV (1R)-1-(6-Methylpyridazin-3-yl)ethan-1-aminehydrochloride

(S)-2-methyl-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]propane-2-sulfinamide(21.3 g, 88.3 mmol) was dissolved in methanol (400 mL) and cooled to 0°C. prior to slow addition of 12M HCl in water (73.6 mL, 883 mmol). Thereaction was stirred at room temperature for 1 hour before evaporationunder vacuum. The residue was azeotroped twice with isopropanol (100 mL)and triturated with warm isopropanol (100 mL). After cooling to RT, theprecipitate was collected by filtration and dried under vacuum to give11.8 g (55% yield) of the title compound as an off-white powder.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 8.90 (s, 3H), 8.02 (d, J=8.7 Hz, 1H),7.87 (d, J=8.7 Hz, 1H), 7.58-7.14 (m, 2H), 4.71 (dt, J=12.4, 6.1 Hz,1H), 2.71 (s, 3H), 1.58 (d, J=6.9 Hz, 3H).

Analytical HPLC: Column: Chiralpak AD-H 25 cm; Mobile phase: 90:10Heptane: Ethanol+1% DEA; Flow rate: 1 ml/min; Detection: UV 254 nm;Runtime: 60 mins; Rt=28.64 min; 100% ee.

Intermediate XVI 1-[6-(Trifluoromethyl)pyridazin-3-yl]ethanone

To a degassed solution of 3-chloro-6-(trifluoromethyl)pyridazine (17.26g, 94.6 mmol) and tributyl(1-ethoxyethenyl)stannane (38.3 mL, 113.5mmol) in DMF (400 mL) under N₂ was added PdCl₂(PPh₃)₂ (0.66 g, 0.95mmol). The reaction was stirred at 100° C. for 3 h. The cooled reactionmixture was diluted with diethyl ether (800 mL) and treated with aqueousKF solution (27 g of KF in 800 mL water). The mixture was stirredvigorously for 1 h before filtering through celite. The filtrate waswashed with saturated NaHCO₃ solution (400 mL) and brine (400 mL). Theaqueous phase was re-extracted with EtOAc (500 mL) and the combinedorganics dried (over MgSO₄) and concentrated under reduced pressure. Thecrude material was suspended in THF (400 mL) and 2M HCl (400 mL) wasadded. The solution was stirred overnight at RT before beingconcentrated to remove THF and extracted with DCM (3×500 mL). Thecombined organics were dried (over MgSO₄) and concentrated under reducedpressure. The crude material was purified by dry flash silicachromatography (eluting with DCM) to give 11.2 g (61% yield) of thetitle compound as a white solid.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.32 (d, J=8.7 Hz, 1H), 8.00 (d, J=8.7Hz, 1H), 2.95 (s, 3H).

LCMS (Analytical Method A) Rt=1.01 min, MS (ESIpos): m/z=190.9 (M+H)+.

Intermediate XVII(S)-2-Methyl-N-[(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl]propane-2-sulfinamide

To a stirred solution of 1-[6-(trifluoromethyl)pyridazin-3-yl]ethanone(1.27 g, 6.68 mmol) and titanium (IV) ethoxide (2.80 mL, 13.36 mmol) indry THF (27.5 mL) was added (S)-2-t-butylsulfinamide (0.81 g, 6.68 mmol)and the resulting solution stirred at 80° C. for 60 mins. The reactionwas cooled to below −70° C. and L-selectride (1M, 6.7 mL) addeddropwise, keeping the internal temperature below −68° C. After theaddition was complete, the reaction was stirred at this temperature fora further 60 minutes before being quenched by dropwise addition ofmethanol (1.4 mL), followed by EtOAc (40 mL) and water (40 mL). Theorganic layer was collected by decanting and the solid residue stirredwith EtOAc (30 mL). The organic layer was collected by decantation andthe process repeated three times. The combined organics were dried (overNa₂SO₄), filtered, diluted with heptane (20 mL) and evaporated ontosilica (5 g). The material was purified by dry flash chromatography(eluting with TBME, followed by EtOAc then acetone) to give 1.09 g (51%yield) of the title compound as an off-white powder.

¹H NMR (500 MHz, CDCl₃) δ [ppm]=7.81 (d, J=8.7 Hz, 1H), 7.75 (d, J=8.7Hz, 1H), 5.01 (p, J=6.7 Hz, 1H), 3.93 (d, J=5.8 Hz, 1H), 1.75 (d, J=6.9Hz, 3H), 1.23 (s, 9H).

Intermediate XVIII (1R)-1-[6-(Trifluoromethyl)pyridazin-3-yl]ethanaminehydrochloride (1:1)

To a solution of(S)-2-methyl-N-[(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl]propane-2-sulfinamide(998 mg, 3.38 mmol) in methanol (12 mL) at 0° C. was added concentratedHCl (12 M, 2.8 mL, 883 mmol) and the reaction stirred for 1 h at RT. Thereaction mixture was concentrated under reduced pressure and azeotropedwith isopropanol (2×30 mL). The residue was triturated with dry acetoneand the precipitate collected by vacuum filtration. The mother liqueurwas concentrated and the residue triturated with EtOAc. The precipitatewas collected by vacuum filtration and the batches combined to give 738mg (89% yield) of the title compound as an off-white powder.

¹H NMR (500 MHz, DMSO-d6) δ[ppm]=8.95 (s, 3H), 8.42 (d, J=8.8 Hz, 1H),8.27 (d, J=8.8 Hz, 1H), 4.88 (q, J=6.8 Hz, 1H), 1.63 (d, J=6.9 Hz, 3H).

Intermediate XIX Tert-butyl[(2R)-1-(2-acetylhydrazinyl)-1-oxopropan-2-yl]carbamate

N-Boc-D-alanine (1 g, 5.29 mmol) was dissolved in DCM (15 mL). EEDQ (1.3g, 5.29 mmol) was added in one portion, followed by acetic hydrazide(0.47 g, 6.34 mmol) and the solution stirred for 72 h. The reactionmixture was concentrated under reduced pressure and the resultingresidue purified by Biotage Isolera™ chromatography (eluting with20-100% acetone in heptane on a 25 g pre-packed KP-SiO₂ column) to give917.7 mg (71% yield) of the title compound as a white solid.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.95 (s, 1H), 8.29 (s, 1H), 5.06 (d,J=7.2 Hz, 1H), 4.30 (s, 1H), 2.06 (s, 3H), 1.45 (s, 9H), 1.40 (d, J=7.2Hz, 3H).

Intermediate XX Tert-butyl[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]carbamate

Tert-butyl [(2R)-1-(2-acetylhydrazinyl)-1-oxopropan-2-yl]carbamate(917.7 mg, 3.74 mmol) was dissolved in dry THF (50 mL) and Lawesson'sReagent (1.66 g, 4.12 mmol) added in one portion. The resultingsuspension was heated at reflux for 2 h and allowed to cool to RTovernight. The evaporated crude residue was part-purified by BiotageIsolera™ chromatography (eluting with 0-50% EtOAc in heptane on a 25 gpre-packed (solute Silica gel column) to give a yellow gum. Purificationwas performed by dissolving in EtOAc (20 mL) and stirring withdecolourising charcoal (2×4 g) for 10 minutes. The filtrate wasconcentrated under reduced pressure to give 876.6 mg (96% yield) of thetitle compound as a clear gum that crystallised on standing.

¹H NMR (500 MHz, Chloroform-d): δ 5.32-5.04 (m, 2H), 2.75 (s, 3H), 1.65(d, J=6.6 Hz, 3H), 1.45 (s, 9H).

LCMS (Analytical Method A) Rt=1.04 min, MS (ESIpos): m/z=244.0 (M+H)⁺.

Intermediate XXI (1R)-1-(5-Methyl-1,3,4-thiadiazol-2-yl)ethanaminehydrochloride

To a 0° C. solution of tert-butyl[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]carbamate (876.6 mg, 3.6mmol) in MeOH (12 mL) was added 4 M HCl in dioxane (9 mL, 36.0 mmol).After stirring for 4 h at RT the solvent was evaporated and the residuetriturated from Et₂O. The precipitate was collected by filtration anddried in a vacuum oven to give 565 mg (81% yield) of the title compoundas a white solid.

1H NMR (250 MHz, DMSO-d6): δ 7.21 (s, 3H), 4.77-4.63 (m, 1H), 2.71 (s,3H), 1.51 (d, J=6.7 Hz, 3H).

Analytical HPLC: Column: YMC Amy-C (150 mm×4.6 mm, 5 um); Mobile phase:Heptane/Ethanol (1:1) (DEA was added as a modifier); Flow rate: 1ml/min;

Detection: UV 254 nm.; Runtime: 10 mins; Rt=5.13 min; 92.1% ee.

Intermediate XXII 2-(Trifluoromethyl)pyrimidine-5-carbaldehyde

N-Methoxy-N-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamide (1 g,4.25 mmol) was dissolved in anhydrous THF (25 mL) under N₂ and cooled to−78° C. Lithium aluminium hydride (1M in THF, 2.66 mL, 6.34 mmol) wasadded dropwise and the reaction stirred for 30 mins. The reaction wasquenched by addition of water (5 mL) and the reaction mixture allowed towarm to RT. EtOAc (10 mL) and 1M HCl (10 mL) were added and the mixturestirred for 30 mins. The aqueous layer was collected and extracted withEtOAc (10 mL). The combined organics were dried (over MgSO₄) andconcentrated under reduced pressure to give 577.2 mg (77% yield) of thetitle compound as a colourless oil.

¹H NMR (250 MHz, CDCl₃): δ [ppm] 10.26 (s, 1H), 9.35 (s, 2H).

Intermediate XXIII(R)-2-Methyl-N-{(E)-[2-(trifluoromethyl)pyrimidin-5-yl]methylidene}propane-2-sulfinamide

To a solution of 2-(trifluoromethyl)pyrimidine-5-carbaldehyde (0.58 g,3.28 mmol) in DCE (10 mL) was added(R)-(+)-2-methyl-2-propanesulfinamide (0.44 g, 3.60 mmol) and copper(II)sulfate (1.05 g, 6.55 mmol). The mixture was heated to 50° C. andstirred overnight. The reaction mixture was cooled and filtered throughcelite, washing with DCM. The filtrate was concentrated under reducedpressure to give 697.8 mg (76% yield) of the title compound as a browngum.

¹H NMR (250 MHz, CDCl₃): δ 9.30 (s, 2H), 8.73 (s, 1H), 1.30 (s, 9H).

Intermediate XXIV(R)-2-Methyl-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}propane-2-sulfinamide

To a solution of(R)-2-methyl-N-{(E)-[2-(trifluoromethyl)pyrimidin-5-yl]methylidene}propane-2-sulfinamide(697.8 mg, 2.5 mmol) in THF (10 mL) at −70° C. was added ethylmagnesiumbromide (1M in THF, 2.75 mL, 2.75 mmol). The mixture was stirred at −70°C. for 15 mins. The mixture was quenched with saturated NH₄Cl and thereaction allowed to warm to RT. The solution was extracted with EtOAc(3×10 mL) and the combined organics dried (over MgSO₄) and concentratedunder reduced pressure. The crude material was purified by BiotageIsolera™ chromatography (basic silica gel, eluting with 0-60% EtOAc inheptanes) to give 445.2 mg (52% yield) of the title compound as a yellowgum.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.87 (s, 2H), 4.42 (q, J=6.2 Hz, 1H),3.52 (d, J=5.4 Hz, 1H), 2.12 (tt, J=14.0, 7.3 Hz, 1H), 1.89 (dp, J=14.7,7.4 Hz, 1H), 1.24 (s, 10H), 0.93 (t, J=7.4 Hz, 3H).

LCMS (Analytical Method A) Rt=1.19 min, MS (ESIpos): m/z=310 (M+H)+.

Intermediate XXV(1R)-1-[2-(Trifluoromethyl)pyrimidin-5-yl]propan-1-amine hydrochloride

To a solution of(R)-2-methyl-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}propane-2-sulfinamide(445.2 mg, 1.31 mmol) in diethyl ether (5 mL) was added hydrochloricacid (2M in Et₂O), 3.3 mL, 6.6 mmol) and the reaction stirred at RT for1 h. The precipitate was collected by filtration and dried in the vacuumoven to give 283.0 mg (89% yield) of the title compound as a yellowpowder.

¹H NMR (250 MHz, DMSO): δ [ppm] 9.26 (s, 2H), 8.81 (s, 3H), 4.45 (dd,J=8.5, 6.4 Hz, 1H), 2.19-1.89 (m, 2H), 0.85 (t, J=7.4 Hz, 3H).

Intermediate XXVI(R)-2-Methyl-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}propane-2-sulfinamide

To a stirred solution of 1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanone(331 mg, 1.74 mmol) and titanium (IV) ethoxide (0.73 mL, 3.5 mmol) inTHF (10 mL) was added (R)-2-t-butylsulfinamide (211 mg, 1.74 mmol) andthe resulting solution stirred at 80° C. for 45 mins. The reactionmixture was cooled to −78° C. and L-selectride (1.74 mL, 1M solution inTHF) added dropwise maintaining an internal temperature below −70° C.The reaction was stirred at −78° C. for a further 30 mins. The reactionwas quenched by addition of MeOH (1 mL) and warmed to RT. Water (50 mL)then EtOAc (100 mL) was added and mixture filtered through glass fibrefilter paper, washing with EtOAc (2×50 mL). The filtrate was separatedand the aqueous layer extracted with EtOAc (2×50 mL). The combinedorganics combined were dried (over Na₂SO₄), filtered and concentratedunder reduced pressure. The crude material was purified by BiotageIsolera™ chromatography (silica gel, eluting with 0-10% MeOH in EtOAc)followed by trituration from TBME to give 170 mg (28% yield) as anoff-white powder.

¹H NMR (500 MHz, CDCl3) δ [ppm]=8.88 (s, 2H), 4.75 (qd, J=6.8, 3.6 Hz,1H), 3.48-3.38 (m, 1H), 1.68-1.62 (m, 3H), 1.24 (s, 9H).

Intermediate XXVII (1S)-1-[2-(Trifluoromethyl)pyrimidin-5-yl]ethanaminehydrochloride (1:1)

(R)-2-Methyl-N-[(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]propane-2-sulfinamide(0.17 g, 0.58 mmol) was dissolved in methanol (5 mL) and cooled to 0° C.Concentrated aqueous HCl (0.55 mL) was added dropwise and the reactionwas stirred at room temperature for 1 hour before being concentratedunder vacuum. The yellow oil obtained was sonicated with diethyl etherto give a white solid that was collected by filtration to give 0.107 g(82% yield) of the title compound as a white solid.

¹H NMR (250 MHz, DMSO-d6) δ[ppm]=9.25 (s, 2H), 8.79 (s, 3H), 4.67 (q,J=6.9 Hz, 1H), 1.63 (d, J=6.9 Hz, 3H).

Analytical HPLC: Column: Chiralpak AD-H 25 cm; Mobile phase: 90:10Heptane: Ethanol; Flow rate: 0.3 ml/min; Detection: UV 254 nm.; Runtime:70 mins; Rt=37.79 min; 100% ee.

Intermediate XXVIII (1R)-1-(2-Methylpyrimidin-5-yl)ethanamine

Intermediate XXVIII has been synthesized following the description inWO2008/130481.

Intermediate XXXIX 2-(Trifluoromethyl)pyrimidine-5-carbonitrile

Intermediate II (1 g, 5.2 mmol), ammonium chloride (0.56, 10.4 mmol) andtriethylamine (1.45 mL, 10.4 mmol) were suspended in 1,4-dioxane. T3P(50% in EtOAc, 7.3 mL, 12.5 mmol) was added and the reaction stirred at100° C. for 24 h. The reaction was re-treated with T3P (50% in EtOAc,3.65 mL, 6.25 mmol) and heated for a further 6 h. The reaction wasre-treated with ammonium chloride (0.56, 10.4 mmol) and triethylamine(1.45 mL, 10.4 mmol) and stirred at 100° C. for 18 h. The reactionmixture was diluted with water (20 mL) and extracted with EtOAc (3×20mL). The combined organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified byBiotage Isolera™ chromatography (silica gel, eluting with heptane-EtOAc,1:0 to 1:1) to afford 642 mg (71% yield) of the title compound as acolourless oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 9.19 (s, 2H).

LCMS (Analytical Method A) Rt=0.96 min.

Intermediate XL 1-[2-(Trifluoromethyl)pyrimidin-5-yl]methanaminehydrochloride

To a solution of Intermediate XXXIX (500 mg, 2.9 mmol) in ethanol (10mL) was added 6 M hydrochloric acid (1 mL), Pd/C (10% wt. 50 mg, 10% byweight) and the resulting mixture stirred under an atmosphere ofhydrogen at room temperature for 3 h. The catalyst was removed byfiltration under reduced pressure and the solids washed with MeOH. Thefiltrate was concentrated under reduced pressure and the residuetriturated with Et₂O to afford 381.3 mg (50% yield) of the titlecompound as an off-white powder.

¹H NMR (250 MHz, DMSO): δ [ppm] 9.22 (s, 2H), 8.71 (s, 3H), 4.22 (s,2H), contains 19 wt % NH₄Cl.

Intermediate XLI 1-[6-(Trifluoromethyl)-3-pyridyl]ethanone

5-Bromo-2-(trifluoromethyl)pyridine (10.0 g, 44.3 mmol), water (40 mL),DMF (120 mL), potassium carbonate (12.2 g, 88.5 mmol),bis(triphenylphosphine)palladium(II) dichloride (621 mg, 2 mol %) andtributyl(1-ethoxyethenyl)stannane (19.2 g, 53.1 mmol) were stirred andheated to 110° C. under nitrogen for 1.5 h. The reaction mixture wascooled down, diluted with diethyl ether (120 mL) and KF (12.8 g in 50 mLof water) was added. The resulting reaction mixture was vigorouslystirred for 1 h before being filtered through Celite®. The organic layerwas then washed with saturated aqueous NaHCO₃ followed by brine and wasthen dried over MgSO₄, filtered and concentrated under reduced pressure.The residue was taken up in THF (200 mL) and 2M HCl (60 mL) and thereaction was stirred at ambient temperature for 40 minutes. The organicswere removed under reduced pressure and the aqueous layer was extractedwith DCM (3×50 mL). The organic layers were combined, dried over MgSO₄,filtered and concentrated under reduced pressure. The crude material waspurified by Biotage Isolera™ chromatography (silica gel, eluting withheptane-EtOAc, 1:0 to 10:1) to afford 4.90 g (56% yield) as a whitecrystalline solid.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 9.25 (d, J=1.3 Hz, 1H), 8.41(dd, J=8.2, 1.6 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 2.70 (s, 3H).

LCMS (Analytical Method A) Rt=1.15 min, MS (ESIpos): m/z=190.0 (M+H)⁺.

Intermediate XLII2-Methyl-N-[(1R)-1-[6-(trifluoromethyl)-3-pyridyl]ethyl]propane-2-sulfinamide

To a stirred solution of Intermediate XLI (5.44 g, 28.8 mmol) andtitanium(IV) ethoxide (18.6 mL, 57.5 mmol) in diethyl ether (120 mL) wasadded (S)-2-t-butylsulfinamide (3.85 g, 31.6 mmol) and the resultingsolution was stirred at reflux under nitrogen for 3 h. The reactionmixture was cooled to room temperature and then to −78° C. and lithiumtri-s-butylborohydride (1M in THF, 34.5 ml, 34.5 mmol) was addeddropwise. The reaction was stirred at −78° C. for 30 minutes. Thereaction was quenched by addition of brine (20 mL) and was allowed towarm up to room temperature prior to filtration through a plug ofCelite® (washing with ethyl acetate). The filtrate was washed with brine(40 mL) and the aqueous layer was extracted once with ethyl acetate (40mL). The organic layers were combined, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was triturated withEt₂O, and the solids collected by vacuum filtration to afford 5.15 g(61% yield) of the title compound as a white solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.71 (d, J=1.6, 1H), 7.83 (dd,J=8.1, 2.0, 1H), 7.66 (d, J=8.1, 1H), 4.70 (qd, J=6.7, 2.6, 1H),3.44-3.39 (m, 1H), 1.58 (d, J=6.8, 3H), 1.21 (s, 9H).

LCMS (Analytical Method A) Rt=1.13 min, MS (ESIpos): m/z=295.05 (M+H)⁺.

Intermediate XLIII (1R)-1-[6-(Trifluoromethyl)pyridin-3-yl]ethanaminehydrochloride

To a solution of Intermediate XLII (5.15 g, 17.5 mmol) in 2-propanol (20mL) cooled to 0° C. in an ice bath, was added conc. HCl (5 mL, 60 mmol).The mixture was allowed to warm to room temperature and after 20 minutesmethanol (5 mL) was added to aid solubility. The reaction was stirredfor 3 hours. The solvent was removed under reduced pressure and theresidue was triturated with diethyl ether and collected by vacuumfiltration to afford 3.28 g (83% yield) of the title compound as a whitepowder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.68 (s, 1H), 7.79 (dd, J=8.1,2.1, 1H), 7.64 (d, J=8.1, 1H), 4.88 (s, 2H), 1.48 (d, J=6.7, 3H), 1.41(s, 9H).

Intermediate XLIV Tert-butyl[(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl]carbamate

To a solution of Intermediate XLIII in DCM (40 mL) was addeddi-tert-butyl dicarbonate (2.91 g, 13.3 mmol) and triethylamine (5.1 mL,36.4 mmol). The reaction mixture was stirred at RT for 4 h before beingwashed with sat. NH₄Cl solution (40 mL). The aqueous phase wasre-extracted with DCM (2×40 mL), and the combined organics were driedover MgSO₄, filtered and concentrated under reduced pressure to afford3.7 g (100% yield) of the title compound as a white powder.

1H NMR (500 MHz, Chloroform-d): δ [ppm] 8.68 (s, 1H), 7.79 (dd, J=8.1,2.1, 1H), 7.64 (d, J=8.1, 1H), 4.88 (s, 2H), 1.48 (d, J=6.7, 3H), 1.41(s, 9H). LCMS (Analytical Method A) Rt=1.37 min, MS (ESIpos): m/z=290.95(M+H)⁺.

Intermediate XLVII Ethyl (5-bromopyrimidin-2-yl)(difluoro)acetate

To a mixture of zinc powder (9.6 g, 147.4 mmol) in triglyme (100 mL) wasadded TMSBr (1.9 mL, 14.4 mmol) under N₂ and the reaction stirred atreflux for 90 minutes. The reaction was cooled to RT, ethylbromo(difluoro)acetate (15.3 mL, 119.3 mmol) was added dropwise, and themixture stirred for 30 minutes before being cooled to ˜10° C.5-Bromo-2-iodo-pyrimidine (10 g, 35.1 mmol) in DMA (100 mL) was addeddropwise, then the reaction allowed to warm to RT. Copper(I) bromide(21.1 g, 147.4 mmol) was added portionwise over 40 minutes, then thereaction stirred at RT for a further 1 h. The reaction mixture waspoured slowly into a cooled mixture of 10% NaCl (100 mL), 5M HCl (100mL) and toluene (200 mL), and stirred for 30 minutes. The mixture wasfiltered, and the organic layer separated and dried over MgSO₄, filteredand concentrated under reduced pressure. The crude material was purifiedby Biotage Isolera™ chromatography (silica gel, eluting withheptane-EtOAc, 1:0 to 7:3) afford 10.34 g (82% yield, 78% purity) of thetitle compound as a colourless oil.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.92 (s, 2H), 4.41 (qd, J=7.1,3.4 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H).

LCMS (Analytical Method A) Rt=1.10 min, MS (ESIpos): m/z=280.9/282.9(M+H)⁺.

Intermediate XLVIII Ethyl (5-acetylpyrimidin-2-yl)(difluoro)acetate

To a degassed solution of Intermediate XLVII (4.5 g, 12.5 mmol) andtributyl(1-ethoxyethenyl)stannane (5.06 mL, 15.0 mmol) in dry DMF (45mL) under N₂ was added PdCl₂(PPh₃)₂ (88 mg, 0.13 mmol). The reaction wasstirred at 100° C. for 3 h. The reaction mixture was diluted with ether(90 mL) and treated with aqueous KF solution (7.26 mg of KF in 90 mlwater). The mixture was stirred vigorously for 1 h before being filteredthrough glass fibre filter paper. The filtrate was washed with saturatedNaHCO₃ solution followed by brine. The aqueous was extracted with EtOAc.The combined organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude material was suspended in THF (90 mL)and 1M HCl (90 mL) was added. The solution was stirred for 2 h at RT,before being concentrated to remove THF, then extracted with DCM (3×90mL). The combined organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified byBiotage Isolera™ chromatography (silica gel, eluting with heptane-EtOAc,3:2 to 1:1) to afford 1.37 g (45% yield) of the title compound as acolourless oil.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 9.32 (s, 2H), 4.41 (q, J=7.1 Hz,2H), 2.70 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).

LCMS (Analytical Method A) Rt=1.01 min, MS (ESIpos): m/z=244.95 (M+H)⁺.

Intermediate XLIX 1-[2-(Difluoromethyl)pyrimidin-5-yl]ethanone

A mixture of Intermediate XLVIII (1.05 g, 4.3 mmol), KF (1.25 g, 21.5mmol) and water (387.3 μL, 21.5 mmol) in DMF (20 mL) was stirred at 170°C. under N₂ for 3 h, then cooled to RT. Saturated NaHCO₃ solution (20mL) was added and the mixture extracted with Et₂O (3×40 mL). Thecombined organics were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 3:2) to afford493 mg (67% yield) of the title compound as a yellow oil whichcrystallised on standing.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 9.33 (s, 2H), 6.71 (t, J=54.2Hz, 1H), 2.70 (s, 3H).

LCMS (Analytical Method A) Rt=0.69 min, MS (ESIpos): m/z=172.90 (M+H)⁺.

Intermediate L(S)—N-[(1R)-1-[2-(Difluoromethyl)pyrimidin-5-yl]ethyl]-2-methylpropane-2-sulfinamide

To a stirred solution of Intermediate XLIX (492 mg, 2.86 mmol) andtitanium(IV) ethoxide (1.84 mL, 3.14 mmol) in Et₂O (20 mL) was added(S)-2-t-butylsulfinamide (381 mg, 3.14 mmol) and the resulting solutionstirred at reflux for 2 h under nitrogen. The reaction mixture wascooled to RT and then to −78° C. and L-selectride (3.7 mL, 1M sol. inTHF) was added dropwise. The reaction was stirred at −78° C. for afurther 45 min, then the reaction was quenched by addition of brine (5mL), before being allowed to warm to RT. The suspension was filteredthrough a plug of Celite®, washing with EtOAc. The filtrate was washedwith brine (10 mL), and the aqueous layer re-extracted with EtOAc (2×10mL). The combined organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was triturated withdiethyl ether to afford 365.1 mg (45% yield) of the title compound as awhite solid.

1H NMR (250 MHz, Chloroform-d): δ [ppm] 8.84 (s, 2H), 6.67 (t, J=54.5Hz, 1H), 4.72 (qd, J=6.7, 3.1 Hz, 1H), 3.41 (d, J=2.6 Hz, 1H), 1.63 (d,J=6.8 Hz, 3H), 1.23 (s, 9H).

LCMS (Analytical Method A) Rt=0.90 min, MS (ESIpos): m/z=277.95 (M+H)⁺.

Intermediate LI (1R)-1-[2-(Difluoromethyl)pyrimidin-5-yl]ethanaminehydrochloride

Intermediate L (982 mg, 3.54 mmol) was stirred in 1 M HCl in ether (35mL) for 4 h to form a white precipitate. The material was collected byfiltration and dried in a vacuum oven to afford 780 mg (90% yield) as ayellow glass.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 9.17 (s, 2H), 8.87 (s, 2H), 7.01 (t,J=53.9 Hz, 1H), 4.68-4.55 (m, 1H), 1.62 (d, J=6.9 Hz, 3H).

Intermediate LII 1-[6-(Difluoromethyl)pyridin-3-yl]ethanone

To a degassed solution of 5-bromo-2-(difluoromethyl)pyridine (1 g, 4.81mmol) and tributyl(1-ethoxyethenyl)stannane (1.95 mL, 5.77 mmol) in DMF(20 mL) under N₂ was added PdCl₂(PPh₃)₂ (34 mg, 0.05 mmol). The reactionwas stirred at 100° C. for 2.5 h. The reaction mixture was diluted withether (40 mL) and treated with aqueous KF solution (1.4 g of KF in 40 mLwater). The mixture was stirred vigorously for 1 h before being filteredthrough Celite®. The filtrate was diluted with ethyl acetate (50 mL),washed with saturated sodium bicarbonate solution, then brine, driedover MgSO₄, filtered and concentrated under reduced pressure. The crudematerial was suspended in THF (20 mL) and 2M HCl (20 mL) was added. Thesolution was stirred vigorously for 15 minutes at RT before beingconcentrated to remove THF, then extracted with DCM (3×50 mL). Thecombined organics were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 4:1) toafford 730 mg (87% yield) of the title compound as a colourless oil.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.20 (d, J=1.6 Hz, 1H), 8.47 (dd,J=8.1, 2.1 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.05 (t, J=54.6 Hz, 1H),2.67 (s, 3H). LCMS (Analytical Method A) Rt=0.94 min, MS (ESIpos):m/z=171.9 (M+H)⁺.

Intermediate LIII(S)—N-[(1R)-1-[6-(Difluoromethyl)pyridin-3-yl]ethyl]-2-methylpropane-2-sulfinamide

To a stirred solution of Intermediate LII (725 mg, 4.19 mmol) andtitanium(IV) ethoxide (2.73 mL, 8.47 mmol) in diethyl ether (40 mL) wasadded (S)-2-t-butylsulfinamide (565 mg, 8.47 mmol) and the resultingsolution stirred at reflux for 20 h under nitrogen. The reaction mixturewas cooled to RT then further cooled to −78° C. and L-selectride (4.66mL, 1M sol. in THF) was added dropwise. The reaction was stirred at −78°C. for a further 1 h then quenched by addition of brine (25 mL), beforebeing allowed to warm to RT. The suspension was filtered through a plugof Celite®, washing with ethyl acetate. The filtrate was washed withbrine (20 mL), and the aqueous layer re-extracted with EtOAc (30 mL).The combined organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude yellow solid was triturated withdiethyl ether to afford 525 mg (44% yield) of the title compound as awhite solid.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 8.67 (d, J=1.7 Hz, 1H), 7.96 (dd,J=8.1, 2.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 6.93 (t, J=55.0 Hz, 1H),5.58 (d, J=5.6 Hz, 1H), 4.56 (m, 1H), 1.51 (d, J=6.8 Hz, 3H), 1.11 (s,9H).

LCMS (Analytical Method A) Rt=0.99 min, MS (ESIpos): m/z=276.95 (M+H)⁺.

Intermediate LIV (1R)-1-[6-(Difluoromethyl)pyridin-3-yl]ethanaminehydrochloride

To a solution of Intermediate LIII (517 mg, 2.23 mmol) in methanol (2mL) cooled to 0° C. in an ice bath, was added 5M HCl in 2-propanol (1.87mL, 9.35 mmol). The mixture was allowed to warm to room temperature andwas stirred for 1 hour. The solvent was removed under reduced pressureand the residue triturated in diethyl ether to afford 450 mg (97% yield)of the title compound as a white solid.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 8.84-8.79 (m, 1H), 8.65 (s, 3H), 8.18(d, J=8.2 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 6.98 (t, J=54.8 Hz, 1H), 4.57(m, 1H), 1.57 (d, J=6.9 Hz, 3H).

Intermediate LV Methyl (2R)-2-(tert-butoxycarbonylamino)propanoate

To a solution of D-alanine methyl ester hydrochloride (5 g, 35.8 mmol)and sodium hydrogen carbonate (9.0 g, 107 mmol) in water (100 mL) wasadded di-tert-butyl dicarbonate (11.7 g, 53.7 mmol) and the resultingsolution was stirred at RT overnight. The reaction mixture was extractedwith DCM (3×100 mL) and the combined organics were dried over MgSO₄,filtered and concentrated under reduced pressure. Crude NMR revealedlarge amounts of un-reacted di-tert-butyl dicarbonate, hence thematerial was taken up in DCM (50 mL) and treated with N,N-dimethylethylenediamne (5 mL), and stirred for 30 mins. The solution was washedwith 1M HCl (50 mL), dried over MgSO₄, filtered and concentrated underreduced pressure to afford 5.35 g (73% yield) of the title compound as acolourless oil.

¹H NMR (500 MHz, Chloroform-d) δ 5.04 (s, 1H), 4.31 (m, 1H), 3.73 (s,3H), 1.44 (s, 9H), 1.37 (d, J=7.2 Hz, 3H).

Intermediate LVI Tert-butyl [(2R)-1-hydrazino-1-oxopropan-2-yl]carbamate

To a solution of Intermediate LV (5.35 g, 26.3 mmol) in ethanol (140 mL)was added hydrazine hydrate (19.8 mL) and the reaction was stirred at RTfor 5 h. The reaction mixture was concentrated under reduced pressureand the residue was triturated with heptane. The resulting precipitatewas collected by filtration and dried in the vacuum oven to afford 5.00g (93% yield) of the title compound as a white crystalline powder.

¹H NMR (250 MHz, DMSO): δ [ppm] 8.96 (s, 1H), 6.81 (d, J=7.7 Hz, 1H),4.17 (s, 2H), 4.03-3.81 (m, 1H), 1.36 (s, 9H), 1.14 (d, J=7.1 Hz, 3H).

Intermediate LVII Tert-butyl{(2R)-1-oxo-1-[2-(trifluoroacetyl)hydrazino]propan-2-yl}carbamate

To a solution of Intermediate LVI (3.96 g, 19.5 mmol) and DIPEA (4.07mL, 23.4 mmol) in MeCN (100 mL) at −45° C. under N₂ was addedtrifluoroacetic anhydride (3.03 mL, 21.4 mmol). The reaction wasgradually warmed to RT and further stirred for 30 mins. The solvent wasremoved by evaporation and the residue partitioned between H₂O (25 mL)and EtOAc (25 mL). The organic phase was separated and the aqueous phasewas re-extracted with EtOAc (25 mL). The combined organic phases werewashed with H₂O (30 mL), brine (30 mL), dried over MgSO₄ and evaporated,and the residue was purified by flash column chromatography (silica gel,eluting with heptane-EtOAc, 3:2) to afford 4.30 g (69% yield) of thetitle compound as a white solid foam.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 9.16 (s, 1H), 8.89 (s, 1H), 4.93(s, 1H), 4.39-4.22 (m, 1H), 1.46 (s, 9H), 1.42 (d, J=7.1 Hz, 3H).

LCMS (Analytical Method A) Rt=0.90 min, MS (ESIpos): m/z=321.95 (M+Na)⁺.

Intermediate LVIII Tert-butyl{(1R)-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}carbamate

Intermediate LVII (1.25 g, 4.18 mmol) was dissolved in dry THF (50 mL)and Lawesson's Reagent (1.86 g, 4.6 mmol) was added in one portion. Theresulting suspension was then heated to reflux for 2 h then concentratedunder reduced pressure. The residue was purified by Biotage Isolera™chromatography (eluting with 10-25% EtOAc in heptane on a pre-packedKP-SiO₂ column). The product containing fractions were combined anddecolourised with ˜5 g activated charcoal (stirring for 1 h). Themixture was filtered and concentrated under reduced pressure to give0.63 g (51% yield) of the title compound as a white powder.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 5.30-5.21 (m, 1H), 5.17 (s, 1H),1.74 (d, J=6.9 Hz, 3H), 1.46 (s, 9H).

LCMS (Analytical Method A) Rt=1.18 min, MS (ESIpos): m/z=241.85 (M+H)⁺.

Intermediate LIX(1R)-1-[5-(Trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethanaminehydrochloride

Intermediate LVIII (571 mg, 1.92 mmol) was stirred in hydrochloric acid,4M in 1,4-dioxane (4.5 mL, 16 mmol) for 2 h. The solution wasconcentrated under reduced pressure, and the residue triturated withEt₂O to afford 384 mg (86% yield) of the title compound as a whitepowder.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 9.03 (s, 3H), 5.20 (q, J=6.8 Hz, 1H),1.71 (d, J=6.8 Hz, 3H).

Example 13-(Cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a stirred solution of Intermediate 5A (46 mg, 0.16 mmol),Intermediate VI (40.1 mg, 0.176 mmol), DIPEA (0.111 mL, 0.64 mmol) andDMAP (3.9 mg, 0.032 mmol) in DCM (2 mL) was added HATU (73.0 mg, 0.192mmol) at RT. After stirring for 2 h at RT, the reaction mixture waswashed with water (3 mL) and the aqueous layer re-extracted with DCM(2×3 mL). The combined organics were dried (over MgSO₄) and evaporatedat reduced pressure. Crude material was purified by crystallisation fromacetonitrile to give 43.4 mg (59% yield) of the title compound as awhite powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.84 (s, 1H),7.55-7.53 (m, 1H), 7.53-7.51 (m, 1H), 7.42-7.35 (m, 1H), 6.62 (d, J=6.6Hz, 1H), 5.36 (p, J=7.1 Hz, 1H), 3.91 (d, J=7.0 Hz, 2H), 2.53 (s, 3H),1.71 (d, J=7.2 Hz, 3H), 1.36-1.22 (m, 1H), 0.71-0.63 (m, 2H), 0.37 (q,J=4.9 Hz, 2H).

Analytical LC-MS (Analytical Method D) 99%® Rt=4.57, MH+=463.

Example 23-(Cyclopropylmethoxy)-N-[(6-methylpyridazin-3-yl)methyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

In analogy to Example 1, reaction of 50 mg Intermediate 5A with 22 mg(0.18 mmol) 1-(6-methylpyridazin-3-yl)methanamine and subsequentpurification by preparative HPLC (Method A) gave 38.2 mg (59% yield) ofthe title compound.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.92 (t, J=1.4 Hz, 1H), 7.65 (m,J=5.3 Hz, 1H), 7.62 (dd, J=2.4, 1.5 Hz, 1H), 7.54 (d+s, J=8.6 Hz, 2H),7.47 (dd, J=2.3, 1.5 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 4.95 (d, J=5.3 Hz,2H), 3.95 (d, J=6.9 Hz, 2H), 2.76 (s, 3H), 2.54 (d, J=1.1 Hz, 3H),1.36-1.28 (m, 1H), 0.72-0.66 (m, 2H), 0.40 (q, J=4.7 Hz, 2H).

Analytical LC-MS (Analytical Method F): 98.5%® Rt=2.90, MH+=395.

Example 33-(Cyclopropylmethoxy)-N-[(5-methylpyrazin-2-yl)methyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a suspension of sodium3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (50 mg,0.16 mmol), 1-(5-methylpyrazin-2-yl)methanamine (22 mg, 0.18 mmol) andDMAP (4 mg, 0.03 mmol) in DCM (1 mL) was added DIPEA (84 μL, 0.48 mmol)and HATU (73 mg, 0.19 mmol) and the reaction stirred for 18 h. Thereaction mixture was diluted with DCM (4 mL) and washed with saturatedaq. NaHCO₃ (2×2 mL), brine (2 mL), dried (over MgSO₄) and concentratedin vacuo. The crude material was purified by preparative HPLC (Method A)to give 36 mg (55% yield) of the title compound.

¹H NMR (500 MHz, CDCl₃): δ [ppm]=8.57-8.51 (m, 1H), 8.40 (s, 1H), 7.87(d, J=1.3 Hz, 1H), 7.58-7.55 (m, 1H), 7.50 (d, J=1.1 Hz, 1H), 7.44-7.41(m, 1H), 7.29 (s, 1H), 4.76 (d, J=5.2 Hz, 2H), 3.91 (d, J=6.9 Hz, 2H),2.57 (s, 3H), 2.51 (d, J=0.9 Hz, 3H), 1.29 (dqt, J=9.5, 7.1, 4.8 Hz,1H), 0.69-0.64 (m, 2H), 0.37 (q, J=4.8 Hz, 2H).

LCMS (Analytical Method F) Rt=3.19 min, MS (ESIpos) m/z=395 (M+H)⁺.

Example 43-(Cyclopropylmethoxy)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a suspension of sodium3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (50 mg,0.16 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanamine hydrochloride (30mg, 0.18 mmol) and DMAP (4 mg, 0.03 mmol) in DCM (1 mL) was added DIPEA(84 μL, 0.48 mmol) and HATU (73 mg, 0.19 mmol) and the reaction stirredfor 18 h. The reaction mixture was diluted with DCM (4 mL) and washedwith saturated aq. NaHCO₃ (2×2 mL), brine (2 mL), dried (over MgSO₄) andconcentrated in vacuo. The crude material was purified by preparativeHPLC (Method A) to give 43 mg (63% yield) of the title compound.

¹H NMR (500 MHz, CDCl₃): δ [ppm]=8.52 (d, J=1.3 Hz, 1H), 8.40 (s, 1H),7.86 (d, J=1.3 Hz, 1H), 7.58-7.53 (m, 1H), 7.50 (d, J=1.1 Hz, 1H),7.43-7.38 (m, 1H), 7.31 (d, J=7.5 Hz, 1H), 5.42 (p, J=6.9 Hz, 1H), 3.91(d, J=7.0 Hz, 2H), 2.56 (s, 3H), 2.51 (d, J=0.9 Hz, 3H), 1.59 (d, J=6.8Hz, 3H), 1.34-1.24 (m, 1H), 0.68-0.63 (m, 2H), 0.36 (q, J=4.8 Hz, 2H).

LCMS (Analytical Method F) Rt=3.42 min, MS (ESIpos) m/z=409 (M+H)⁺.

Example 5N-[1-(3-Chloro-5-fluoropyridin-2-yl)ethyl]-3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a suspension of sodium3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (47.5 mg,0.15 mmol), 1-(3-chloro-5-fluoropyridin-2-yl)ethanamine hydrochloride(35 mg, 0.17 mmol) and DMAP (4 mg, 0.03 mmol) in DCM (1 mL) was addedDIPEA (80 μL, 0.46 mmol) and HATU (70 mg, 0.18 mmol) and the reactionstirred for 2.5 h. The reaction mixture was diluted with DCM (4 mL) andwashed with saturated aq. NaHCO₃ (2×2 mL), brine (2 mL), dried (overMgSO₄) and concentrated in vacuo. The crude material was purified bypreparative HPLC (Method A) then triturated with diethylether to give 31mg (59% yield) of the title compound as a mixture of two enantiomers.

¹H NMR (500 MHz, CDCl₃): δ [ppm]=8.39 (d, J=2.5 Hz, 1H), 7.90 (t, J=1.4Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.58 (dd, J=2.4, 1.5 Hz, 1H), 7.54-7.49(m, 2H), 7.44 (dd, J=2.4, 1.5 Hz, 1H), 5.76 (p, J=6.6 Hz, 1H), 3.93 (d,J=7.0 Hz, 2H), 2.53 (d, J=1.1 Hz, 3H), 1.53 (d, J=5.6 Hz, 3H), 1.30 (td,J=7.9, 4.0 Hz, 1H), 0.71-0.64 (m, 2H), 0.38 (q, J=4.8 Hz, 2H).

LCMS (Analytical Method F) Rt=4.18 min, MS (ESIpos) m/z=446 (M+H)⁺.

Example 6N-[1-(5-Chloro-3-fluoropyridin-2-yl)ethyl]-3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a suspension of sodium3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (47.5 mg,0.15 mmol), 1-(5-chloro-3-fluoropyridin-2-yl)ethanamine hydrochloride(35 mg, 0.17 mmol) and DMAP (4 mg, 0.03 mmol) in DCM (1 mL) was addedDIPEA (80 μL, 0.46 mmol) and HATU (70 mg, 0.17 mmol) and the reactionstirred for 2.5 h. The reaction mixture was diluted with DCM (4 mL) andwashed with saturated aq. NaHCO₃ (2×2 mL), brine (2 mL), dried (overMgSO₄) and concentrated in vacuo. The crude material was purified bypreparative HPLC (Method A) then triturated with acetonitrile to give 30mg (43% yield) of the title compound as a mixture of two enantiomers.

¹H NMR (500 MHz, CDCl₃): δ [ppm]=8.38 (d, J=1.8 Hz, 1H), 7.89 (t, J=1.4Hz, 1H), 7.58 (dd, J=2.4, 1.5 Hz, 1H), 7.57-7.51 (m, 2H), 7.47 (dd,J=8.9, 2.0 Hz, 1H), 7.43 (dd, J=2.4, 1.5 Hz, 1H), 5.70-5.62 (m, 1H),3.93 (d, J=7.0 Hz, 2H), 2.53 (d, J=1.1 Hz, 3H), 1.55 (d, J=6.7 Hz, 3H),1.31 (ddd, J=12.8, 8.0, 5.3 Hz, 1H), 0.70-0.64 (m, 2H), 0.38 (q, J=4.7Hz, 2H).

LCMS (Analytical Method F) Rt=4.19 min, MS (ESIpos) m/z=446 (M+H)⁺.

Example 73-(Cyclopropylmethoxy)-N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a solution of3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid (58 mg,0.2 mmol), (1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethanaminehydrochloride (43 mg, 0.24 mmol) and DIPEA (0.174 mL, 1.0 mmol) in DCM(2 mL) was added T3P (0.23 mL, 0.4 mmol, 50% solution in EtOAc) and thereaction mixture stirred at RT for 2 h. The reaction mixture washed with2M NaOH (2 mL) and the aqueous layer further extracted with DCM (2×2mL). The combined organics were dried (over MgSO₄) and concentratedunder reduced pressure. The material was triturated from Et₂O to give46.8 mg (54% yield) of the title compound as a white powder.

¹H NMR (500 MHz, CDCl₃): δ [ppm]=7.84 (t, J=1.4 Hz, 1H), 7.57 (dd,J=2.4, 1.5 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.41 (dd, J=2.3, 1.6 Hz,1H), 6.99 (d, J=7.5 Hz, 1H), 5.68 (p, J=7.0 Hz, 1H), 3.92 (d, J=6.9 Hz,2H), 2.76 (s, 3H), 2.52 (d, J=1.1 Hz, 3H), 1.79 (d, J=6.9 Hz, 3H),1.35-1.24 (m, 1H), 0.70-0.63 (m, 2H), 0.37 (q, J=4.7 Hz, 2H).

LCMS (Analytical Method F) Rt=3.33 min, MS (ESIpos): m/z=415 (M+H)⁺.

Example 83-(Cyclopropylmethoxy)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a solution of3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid (46 mg,0.16 mmol), (1R)-1-(6-methylpyridazin-3-yl)ethanamine hydrochloride(30.6 mg, 0.18 mmol), DIPEA (0.11 mL, 0.64 mmol) and DMAP (3.9 mg, 0.032mmol) in DCM (2 mL) was added HATU (73.0 mg, 0.19 mmol) and the reactionstirred for 2 h at RT. The reaction mixture was diluted with water (3mL) and the aqueous layer re-extracted with DCM (2×3 mL). The combinedorganics were dried (over MgSO₄) and concentrated under reducedpressure. The crude material was purified preparative HPLC (Method A)then triturated from Et₂O to give 29.7 mg (45% yield) of the titlecompound as a white powder.

¹H NMR (500 MHz, CDCl₃): δ [ppm]=7.90-7.86 (m, 1H), 7.73 (d, J=7.4 Hz,1H), 7.60-7.57 (m, 1H), 7.51 (s, 1H), 7.44-7.42 (m, 1H), 7.40 (d, J=8.5Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 5.46 (p, J=7.2 Hz, 1H), 3.92 (d, J=6.9Hz, 2H), 2.73 (s, 3H), 2.52 (s, 3H), 1.68 (d, J=6.8 Hz, 3H), 1.35-1.23(m, 1H), 0.71-0.61 (m, 2H), 0.37 (q, J=4.8 Hz, 2H).

LCMS (Analytical Method D) Rt=3.96 min, MS (ESIpos) m/z=409 (M+H)⁺.

Example 93-(Cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

To a solution of3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid (60 mg,0.21 mmol), (1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethanaminehydrochloride (51 mg, 0.22 mmol) and DIPEA (144 μL, 0.83 mmol) in DCM (1mL) was added HATU (95 mg, 0.25 mmol) and the reaction mixture stirredat RT for 2 h. The mixture was diluted with DCM (1 mL) and washed withwater (2×2 mL). The aqueous phase was re-extracted with DCM (2 mL) andthe combined organics dried (over Na₂SO₄) and concentrated in vacuo. Thecrude product was purified by preparative HPLC (Method A) to give 61.2mg (64% yield) of the title compound as a white powder.

¹H NMR (500 MHz, CDCl₃): δ [ppm]=7.88 (s, 1H), 7.82 (d, J=8.7 Hz, 1H),7.74 (d, J=8.7 Hz, 1H), 7.59-7.54 (m, 1H), 7.51 (d, J=1.1 Hz, 1H),7.48-7.38 (m, 2H), 5.60 (p, J=7.0 Hz, 1H), 3.91 (d, J=6.9 Hz, 2H), 2.52(d, J=0.9 Hz, 3H), 2.00 (s, 1H), 1.76 (d, J=7.0 Hz, 3H), 1.29 (dtd,J=14.7, 7.4, 6.8, 4.7 Hz, 1H), 0.70-0.61 (m, 2H), 0.37 (q, J=4.8 Hz,2H).

LCMS (Analytical Method F) Rt=3.84 min, MS (ESIpos) m/z=463 (M+H)⁺.

Example 103-(Cyclopropylmethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a suspension of sodium3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (50 mg,0.16 mmol), (1R)-1-(2-methylpyrimidin-5-yl)ethanamine (24 mg, 0.18 mmol)and DMAP (4 mg, 0.03 mmol) in DCM (1 mL) was added DIPEA (85 μL, 0.48mmol) and HATU (73 mg, 0.19 mmol) and the reaction stirred for 2 h. Thereaction mixture was diluted with DCM (4 mL), washed with saturated aq.NaHCO₃ (2×2 mL), brine (2 mL) and the organic phase dried (over MgSO₄)and concentrated in vacuo to give 37.4 mg (56% yield) of the titlecompound. ¹H NMR (500 MHz, CDCl₃) δ [ppm]=8.69 (s, 2H), 7.85 (s, 1H),7.56-7.48 (m, 2H), 7.39 (dd, J=2.3, 1.6 Hz, 1H), 6.53 (d, J=6.8 Hz, 1H),5.30 (p, J=7.2 Hz, 1H), 3.91 (d, J=6.9 Hz, 2H), 2.73 (s, 3H), 2.53 (d,J=1.1 Hz, 3H), 1.66 (d, J=7.1 Hz, 3H), 1.34-1.24 (m, 1H), 0.69-0.62 (m,2H), 0.39-0.33 (m, 2H).

LCMS (Analytical Method F) Rt=3.17 min, MS (ESIpos) m/z=409 (M+H)⁺.

Example 113-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid, i.e. Intermediate 5B, (6.8 g, 22.3 mmol), Intermediate VI (6.8 g,26.7 mmol) and DIPEA (15.5 mL, 89.1 mmol) in DCM (100 mL) was added T3P(19.5 mL, 33.4 mmol, 50% in EtOAc) and the reaction mixture stirred atRT for 2 h. The reaction mixture was washed with 1M NaOH (100 mL) andthe aqueous layer re-extracted with DCM (2×50 mL). The combined organicswere dried (over MgSO₄) and concentrated under reduced pressure. Theresidue was triturated with Et₂O to give 7.51 g (70% yield) of the titlecompound as a white powder.

¹H NMR (500 MHz, CDCl₃): δ [ppm]=8.93 (s, 2H), 7.85 (t, J=1.4 Hz, 1H),7.53-7.52 (m, 1H), 7.51 (dd, J=2.4, 1.5 Hz, 1H), 7.36 (t, J=2.4, 1.6 Hz,1H), 6.64 (d, J=6.5 Hz, 1H), 5.36 (p, J=7.1 Hz, 1H), 5.08-5.03 (m, 1H),4.05-3.97 (m, 3H), 3.91 (td, J=8.4, 4.3 Hz, 1H), 2.54 (d, J=1.1 Hz, 3H),2.27 (dtd, J=14.4, 8.4, 6.1 Hz, 1H), 2.20-2.12 (m, 1H), 1.72 (d, J=7.2Hz, 3H).

LCMS (Analytical Method D) Rt=4.16 min, MS (ESIpos) m/z=479 (M+H)⁺.

Example 12N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid (40 mg, 0.13 mmol), 1-(5-methylpyrazin-2-yl)methanaminedihydrochloride (30.8 mg, 0.16 mmol) and DIPEA (91 μL, 0.52 mmol) in DCM(1 mL) was added HATU (74.7 mg, 0.20 mmol) and the reaction mixturestirred for 2 h at RT. The mixture was diluted with DCM (1 mL), washedwith water (2×1 mL), dried (over a hydrophobic frit) and concentrated invacuo to give yellow oil. The crude material was purified by preparativeHPLC (Method A) to give 35.1 mg (65% yield) of the title compound as ayellow gum.

¹H NMR (500 MHz, CDCl₃): δ [ppm]=8.58 (d, J=1.1 Hz, 1H), 8.44 (s, 1H),7.94 (s, 1H), 7.58 (dd, J=2.3, 1.5 Hz, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.44(dd, J=2.2, 1.5 Hz, 1H), 7.33 (s, 1H), 5.10 (ddt, J=5.9, 4.0, 2.0 Hz,1H), 4.79 (d, J=5.1 Hz, 2H), 4.11-3.98 (m, 3H), 3.94 (td, J=8.4, 4.3 Hz,1H), 2.60 (s, 3H), 2.55 (d, J=1.1 Hz, 3H), 2.36-2.26 (m, 1H), 2.24-2.14(m, 1H).

LCMS (Analytical Method D) Rt=3.66 min, MS (ESIpos) m/z=411 (M+H)⁺.

Example 13N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (70 mg, 0.23 mmol), (+/−)1-(3-chloro-5-fluoropyridin-2-yl)ethanamine (44 mg, 0.25 mmol), DIPEA(119 mg, 0.92 mmol) and HATU (123 mg, 0.32 mmol) were dissolved in DMF(3.1 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. Crude material was purified bypreparative HPLC (method 1, rt: 1.27 min) to afford the title compound65 mg (60% yield) as a mixture of two diastereoisomers.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.49 (d, J=6.84 Hz, 3 H) 1.95-2.05 (m,1 H) 2.25 (d, J=7.86 Hz, 1 H) 3.73-3.95 (m, 4 H) 5.15-5.24 (m, 1 H) 5.54(t, J=6.97 Hz, 1 H) 7.51 (d, J=1.52 Hz, 2 H) 7.64 (d, J=1.27 Hz, 1 H)7.93 (q, J=1.27 Hz, 1 H) 8.09 (dd, J=8.49, 2.66 Hz, 1 H) 8.58 (d, J=2.53Hz, 1 H) 9.08 (d, J=7.35 Hz, 1 H).

Example 14N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (74 mg, 0.24 mmol), (+/−)1-(5-chloro-3-fluoropyridin-2-yl)ethanamine (47 mg, 0.27 mmol), DIPEA(126 mg, 0.97 mmol) and HATU (130 mg, 0.34 mmol) were dissolved in DMF(3.2 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. Crude material was purified bypreparative HPLC (method 1, rt: 1.27 min) to afford the title compound65 mg (57% yield) as a mixture of two diastereoisomers.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.51 (d, J=7.10 Hz, 3 H) 1.94-2.05 (m,1 H) 2.19-2.31 (m, 1 H) 3.73-3.95 (m, 4 H) 5.15-5.24 (m, 1 H) 5.42 (t,J=6.97 Hz, 1 H) 7.47-7.54 (m, 2 H) 7.64 (d, J=1.27 Hz, 1 H) 7.90-7.96(m, 1 H) 8.06 (dd, J=10.01, 1.90 Hz, 1 H) 8.49 (d, J=1.77 Hz, 1 H) 9.10(d, J=7.10 Hz, 1 H).

Example 15N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (80 mg, 0.26 mmol),(1R)-1-(5-chloropyridin-2-yl)ethanamine hydrochloride (56 mg, 0.29mmol), DIPEA (135 mg, 1.05 mmol) and HATU (139 mg, 0.37 mmol) weredissolved in DMF (3.5 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. Crude material waspurified by preparative HPLC (method 1, rt: 1.21 min) to afford thetitle compound 60 mg (51% yield).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.52 (d, J=7.16 Hz, 3 H) 1.94-2.06 (m,1 H) 2.26 (d, J=7.72 Hz, 1 H) 3.75-3.95 (m, 4 H) 5.15-5.26 (m, 2 H) 7.46(d, J=8.48 Hz, 1 H) 7.53 (d, J=1.13 Hz, 2 H) 7.65 (d, J=1.32 Hz, 1 H)7.90 (dd, J=8.48, 2.64 Hz, 1 H) 7.93-7.98 (m, 1 H) 8.58 (d, J=2.07 Hz, 1H) 9.08 (d, J=7.54 Hz, 1 H).

Example 16N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (80 mg, 0.26 mmol),(1R)-1-(5-methylpyrazin-2-yl)ethanamine (40 mg, 0.29 mmol), DIPEA (135mg, 1.05 mmol) and HATU (139 mg, 0.37 mmol) were dissolved in DMF (3.5mL). The reaction mixture was stirred at RT until complete conversionand evaporated to dryness. Crude material was purified by preparativeHPLC (method 1, rt: 1.04 min) to afford the title compound 40 mg (35%yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.54 (d, J=7.07 Hz, 3 H) 1.96-2.05 (m,1 H) 2.20-2.31 (m, 1 H) 2.47 (s, 3 H) 3.75-3.94 (m, 4 H) 5.18-5.26 (m, 2H) 7.52 (d, J=1.26 Hz, 2 H) 7.64 (d, J=1.26 Hz, 1 H) 7.94 (t, J=1.39 Hz,1 H) 8.48 (d, J=1.01 Hz, 1 H) 8.56 (d, J=1.26 Hz, 1 H) 9.08 (d, J=7.58Hz, 1 H).

Example 17N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (77 mg, 0.25 mmol),1-(6-methylpyridazin-3-yl)methanamine (34 mg, 0.28 mmol), DIPEA (130 mg,1.0 mmol) and HATU (133 mg, 0.35 mmol) were dissolved in DMF (3.3 mL).The reaction mixture was stirred at RT until complete conversion andevaporated to dryness. Crude material was purified by preparative HPLC(method 1, rt: 0.91 min) to afford the title compound 50 mg (48% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 2.02 (d, J=6.84 Hz, 1 H) 2.26 (dd,J=13.43, 6.08 Hz, 1 H) 2.60 (s, 3 H) 3.73-3.95 (m, 4 H) 4.73 (d, J=5.83Hz, 2 H) 5.14-5.23 (m, 1 H) 7.48-7.57 (m, 4 H) 7.64 (d, J=1.01 Hz, 1 H)7.98 (t, J=1.39 Hz, 1 H) 9.39 (t, J=5.83 Hz, 1 H).

Example 18N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 58 (69 mg, 0.23 mmol), Intermediate XV (43 mg, 0.25 mmol),DIPEA (117 mg, 0.9 mmol) and HATU (120 mg, 0.32 mmol) were dissolved inDMF (3 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. Crude material was purified bypreparative HPLC (method 1, rt: 0.95 min) to afford the title compound30 mg (31% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.58 (d, J=7.10 Hz, 3 H) 2.01 (d,J=6.59 Hz, 1 H) 2.20-2.31 (m, 1 H) 2.59 (s, 3 H) 3.74-3.95 (m, 4 H)5.15-5.25 (m, 1 H) 5.36 (t, J=7.22 Hz, 1 H) 7.49-7.56 (m, 3 H) 7.56-7.67(m, 2 H) 7.95 (t, J=1.39 Hz, 1 H) 9.14 (d, J=7.35 Hz, 1 H).

Example 193-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid (50 mg, 0.16 mmol),(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethanamine hydrochloride (48mg, 0.21 mmol) and DIPEA (113 μL, 0.65 mmol) in DCM (1 mL) was addedHATU (74 mg, 0.20 mmol). The reaction mixture was stirred at RT for 2 hthen diluted with DCM (1 mL) and washed with water (2×2 mL). The aqueousphase was re-extracted with DCM (2 mL) and the combined organics dried(over Na₂SO₄) and concentrated in vacuo. The crude product was purifiedby preparative HPLC (Method A) to give 39.5 mg (51% yield) of the titlecompound as a white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=7.88 (t, J=1.4 Hz, 1H), 7.82 (d,J=8.7 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.54 (dd, J=2.4, 1.5 Hz, 1H),7.51 (d, J=1.2 Hz, 2H), 7.37 (dd, J=2.3, 1.5 Hz, 1H), 5.60 (p, J=7.0 Hz,1H), 5.06 (ddt, J=6.1, 4.0, 1.8 Hz, 1H), 4.06-3.95 (m, 3H), 3.91 (td,J=8.4, 4.2 Hz, 1H), 2.52 (d, J=1.1 Hz, 3H), 2.26 (dtd, J=14.4, 8.4, 6.1Hz, 1H), 2.20-2.11 (m, 1H), 1.76 (d, J=7.0 Hz, 3H)

LCMS (Analytical Method F) Rt=3.32 min, MS (ESIpos) m/z=479 (M+H)⁺.

Example 20N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid (61 mg, 0.2 mmol),(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethanamine hydrochloride (43 mg,0.24 mmol) and DIPEA (0.174 mL, 1.0 mmol) in DCM (2 mL) was added T3P(0.23 mL, 0.4 mmol, 50% in EtOAc) and the reaction mixture stirred at RTfor 2 h. The reaction mixture was washed with 2M NaOH (2 mL) and theaqueous layer further extracted with DCM (2×2 mL). The combined organicphase was dried (over MgSO₄), evaporated and the resulting materialtriturated from Et₂O to give 42.0 mg (49% yield) of the title compoundas a white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=7.85 (t, J=1.4 Hz, 1H), 7.55(dd, J=2.4, 1.5 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.39 (dd, J=2.4, 1.5Hz, 1H), 7.02 (d, J=7.5 Hz, 1H), 5.69 (p, J=7.0 Hz, 1H), 5.08 (td,J=4.2, 2.1 Hz, 1H), 4.07-3.97 (m, 3H), 3.92 (td, J=8.4, 4.2 Hz, 1H),2.76 (s, 3H), 2.53 (d, J=1.1 Hz, 3H), 2.28 (dtd, J=14.4, 8.4, 6.1 Hz,1H), 2.22-2.14 (m, 1H), 1.80 (d, J=7.0 Hz, 3H).

LCMS (Analytical Method F) Rt=2.72 min, MS (ESIpos): m/z=431 (M+H)⁺.

Example 213-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{[6-(trifluoromethyl)pyridazin-3-yl]methyl}benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid (40 mg, 0.13 mmol),1-[6-(trifluoromethyl)pyridazin-3-yl]methanamine monohydrochloride (31mg, 0.14 mmol) and DIPEA (68 μL, 0.52 mmol) in DCM (1 mL) was added T3P(50% solution in EtOAc, 117 μL, 0.20 mmol) and the resulting solutionstirred at RT for 2 h. The reaction mixture was diluted with DCM (1 mL),washed with water (1 mL), dried (over MgSO₄) and concentrated in vacuo.The crude material was purified by preparative HPLC (Method A) to give13 mg (21% yield) of the title compound as a white powder.

¹H NMR (500 MHz, CDCl3) δ [ppm]=7.88 (s, 1H), 7.82 (d, J=2.2 Hz, 2H),7.76 (t, J=5.3 Hz, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 7.39 (s, 1H), 5.04(d, J=5.5 Hz, 3H), 4.04-3.95 (m, 3H), 3.90 (td, J=8.4, 4.2 Hz, 1H), 2.50(s, 3H), 2.30-2.20 (m, 1H), 2.19-2.10 (m, 1H).

LCMS (Analytical Method D) Rt=4.05, m/z=465 (M+H)⁺.

Example 223-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid (61 mg, 0.2 mmol),(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propan-1-amine hydrochloride(58 mg, 0.24 mmol) and DIPEA (0.174 mL, 1.0 mmol) in DCM (2 mL) wasadded T3P (0.23 mL, 0.4 mmol, 50% in EtOAc) and the reaction stirred atRT for 4 h. The reaction mixture was washed with saturated NaHCO₃solution (2 mL) and the aqueous layer further extracted with DCM (2×2mL). The combined organics were dried (over MgSO₄) and concentratedunder reduced pressure. The crude material was purified by preparativeHPLC (Method A) and freeze-dried from acetonitrile/water to give 70.6 mg(72% yield) of the title compound as a white powder.

¹H NMR (500 MHz, CDCl3): δ [ppm]=8.91 (s, 2H), 7.85 (s, 1H), 7.53 (d,J=1.1 Hz, 1H), 7.51 (dd, J=2.3, 1.4 Hz, 1H), 7.36-7.34 (m, 1H), 6.62 (d,J=6.8 Hz, 1H), 5.10 (q, J=7.3 Hz, 1H), 5.06 (d, J=2.4 Hz, 1H), 4.04-3.98(m, 3H), 3.91 (td, J=8.4, 4.3 Hz, 1H), 2.54 (d, J=1.0 Hz, 3H), 2.32-2.23(m, 1H), 2.20-2.11 (m, 1H), 2.10-1.96 (m, 2H), 1.08 (t, J=7.4 Hz, 3H).

LCMS (Analytical Method F) Rt=3.60 min, MS (ESIpos): m/z=493.3 (M+H)⁺.

Example 23N-[(1R)-1-(2-Methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (70 mg, 0.23 mmol),(1R)-1-(2-methylpyrimidin-5-yl)ethanamine dihydrochloride (53 mg, 0.25mmol), DIPEA (119 mg, 0.92 mmol) and HATU (122 mg, 0.32 mmol) weredissolved in DMF (3.05 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. Crude material waspurified by preparative HPLC (method 1, rt: 0.97 min) to afford thetitle compound 45 mg (45% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.54 (d, J=7.07 Hz, 3 H) 1.96-2.05 (m,1 H) 2.25 (s, 1 H) 2.59 (s, 3 H) 3.74-3.95 (m, 4 H) 5.12-5.23 (m, 2 H)7.48 (dd, J=2.27, 1.52 Hz, 1 H) 7.50-7.53 (m, 1 H) 7.64 (d, J=1.26 Hz, 1H) 7.91 (t, J=1.52 Hz, 1 H) 8.72 (s, 2 H) 9.04 (d, J=7.58 Hz, 1 H).

Example 24N-[(1R)-1-(6-Methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoicacid (61 mg, 0.2 mmol), (1R)-1-(6-methylpyridin-3-yl)ethanamine (33 mg,0.24 mmol) and DIPEA (0.17 mL, 1.0 mmol) in DCM (2 mL) was added T3P(0.23 mL, 0.4 mmol, 50% in EtOAc) and the reaction mixture stirred at RTfor 2 h. The reaction mixture was washed with 2M NaOH (2 mL) and theaqueous layer further extracted with DCM (2×2 mL). The combined organicswere dried (over MgSO₄) and concentrated under reduced pressure. Thematerial was triturated from Et₂O to give 50.7 mg (60% yield) of thetitle compound as an off-white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.55 (d, J=2.3 Hz, 1H), 7.81 (t,J=1.3 Hz, 1H), 7.60 (dd, J=8.0, 2.4 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H),7.50 (dd, J=2.4, 1.5 Hz, 1H), 7.37 (dd, J=2.3, 1.5 Hz, 1H), 6.44 (d,J=7.4 Hz, 1H), 5.32 (p, J=7.0 Hz, 1H), 5.09-5.03 (m, 1H), 4.06-3.96 (m,3H), 3.91 (td, J=8.4, 4.3 Hz, 1H), 2.55 (s, 3H), 2.53 (d, J=1.1 Hz, 3H),2.32-2.22 (m, 1H), 2.19-2.12 (m, 1H), 1.63 (d, J=7.0 Hz, 4H).

LCMS (Analytical Method D) Rt=3.06, MS (ESIpos) m/z=424 (M+H)⁺.

Example 25N-[(1R)-1-(6-Methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (240 mg, 0.79 mmol), Intermediate XV (191 mg, 1.1 mmol),TEA (0.22 mL, 1.57 mmol) and HATU (329 mg, 0.87 mmol) were dissolved inDMF (12 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. Crude material was purified bypreparative HPLC (System: Labomatic Vario 2000, HPLC pump HD-3000;Column: Chromatex C18 10 μm 125×30 mm; flow rate: 150 ml/min; solvent:acetonitrile/water; A=85%, B=15% to A=0%, B=100%; rt: 6.26-6.77 min) toafford the title compound 150 mg (44% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.59 (d, J=7.07 Hz, 3 H) 1.96-2.07 (m,1 H) 2.20-2.31 (m, 1 H) 2.59 (s, 3 H) 3.75-3.95 (m, 4 H) 5.17-5.24 (m, 1H) 5.37 (t, J=7.20 Hz, 1 H) 7.50-7.56 (m, 3 H) 7.57-7.62 (m, 1 H) 7.64(d, J=1.26 Hz, 1 H) 7.95 (t, J=1.39 Hz, 1 H) 9.13 (d, J=7.58 Hz, 1 H).

Example 263-(5-Methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5C (230 mg, 0.75 mmol),(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethan-1-amine dihydrochloride(239 mg, 0.9 mmol), TEA (0.42 mL, 3.01 mmol) and HATU (430 mg, 1.13mmol) were dissolved in DMF (6.9 mL). The reaction mixture was stirredat RT until complete conversion and evaporated to dryness. Crudematerial was purified by preparative HPLC (System: Labomatic Vario 2000,HPLC pump HD-3000; Column: Chromatex C18 10 μm 125×30 mm; flow rate: 150ml/min; solvent: acetonitrile/water; A=70%, B=30% to A=0%, B=100%; rt:6.46-7.42 min) to afford the title compound 205 mg (57% yield).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.61 (d, J=7.16 Hz, 3 H) 2.02 (d,J=6.03 Hz, 1 H) 2.19-2.33 (m, 1 H) 3.74-3.96 (m, 4 H) 5.15-5.36 (m, 2 H)7.47-7.55 (m, 2 H) 7.65 (d, J=1.13 Hz, 1 H) 7.93 (s, 1 H) 9.09-9.20 (m,3 H).

Example 27N-[(1R)-1-(5-Chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol),(1R)-1-(5-chloropyridin-2-yl)ethanamine hydrochloride (106 mg, 0.55mmol), TEA (0.16 mL, 1.18 mmol) and HATU (164 mg, 0.43 mmol) weredissolved in DMF (4.3 mL). The reaction mixture was stirred at 60° C.until complete conversion and evaporated to dryness. Crude material waspurified by preparative HPLC (method 1, rt: 1.22 min) to afford thetitle compound 100 mg (57% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.53 (d, J=7.10 Hz, 3 H) 1.97-2.07 (m,1 H) 2.20-2.32 (m, 1 H) 3.76-3.95 (m, 4 H) 5.14-5.26 (m, 2 H) 7.47 (d,J=8.36 Hz, 1 H) 7.51-7.56 (m, 2 H) 7.65 (d, J=1.27 Hz, 1 H) 7.91 (dd,J=8.62, 2.53 Hz, 1 H) 7.96 (t, J=1.39 Hz, 1 H) 8.58 (d, J=2.03 Hz, 1 H)9.08 (d, J=7.60 Hz, 1 H).

Example 28N-[(1R)-1-(5-Methylpyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol),(1R)-1-(5-methylpyridin-2-yl)ethanamine hydrochloride (95 mg, 0.55mmol), TEA (0.08 mL, 0.59 mmol) and HATU (164 mg, 0.43 mmol) weredissolved in DMF (3.9 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. Crude material waspurified by preparative HPLC (method 2, rt: 1.15 min) to afford thetitle compound 93 mg (56% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.50 (d, J=7.10 Hz, 3 H) 1.96-2.07 (m,1 H) 2.20-2.31 (m, 4 H) 3.75-3.95 (m, 4 H) 5.12-5.24 (m, 2 H) 7.30 (d,J=7.86 Hz, 1 H) 7.49-7.54 (m, 2 H) 7.55-7.60 (m, 1 H) 7.64 (d, J=1.27Hz, 1 H) 7.95 (t, J=1.39 Hz, 1 H) 8.33-8.40 (m, 1 H) 9.00 (d, J=7.86 Hz,1 H).

Example 29N-[(1R)-1-(5-Methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol),((1R)-1-(5-methylpyrazin-2-yl)ethanamine dihydrochloride (116 mg, 0.55mmol), TEA (0.16 mL, 1.18 mmol) and HATU (164 mg, 0.43 mmol) weredissolved in DMF (4.3 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. Crude material waspurified by preparative HPLC (method 2, rt: 1.04 min) to afford thetitle compound 50 mg (30% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.54 (d, J=7.10 Hz, 3 H) 1.97-2.06 (m,1 H) 2.25 (s, 1 H) 2.47 (s, 3 H) 3.75-3.94 (m, 4 H) 5.17-5.28 (m, 2 H)7.49-7.54 (m, 2 H) 7.64 (d, J=1.27 Hz, 1 H) 7.94 (t, J=1.52 Hz, 1 H)8.49 (d, J=1.01 Hz, 1 H) 8.56 (d, J=1.27 Hz, 1 H) 9.09 (d, J=7.35 Hz, 1H).

In analogy to the procedure described for Example 7 the followingexample was prepared using the appropriate carboxylic acid and amine asstarting materials.

Ex. Structure Name Analytical Data 30

N-[(1R)-1-(6- Methylpyridin- 3-yl)ethyl]-3- (5-methyl-1,3-thiazol-2-yl)-5- [(3S)- tetrahydrofuran- 3-yloxy] benzamide ¹H NMR (500MHz, CDCl₃): δ [ppm] = 8.56 (d, J = 2.2 Hz, 1H), 7.84 (t, J = 1.3 Hz,1H), 7.61 (dd, J = 8.0, 2.3 Hz, 1H), 7.51 (d, J = 1.2 Hz, 2H), 7.50 (dd,J = 2.4, 1.5 Hz, 1H), 7.38 (dd, J = 2.3, 1.5 Hz, 1H), 7.14 (d, J = 8.0Hz, 1H), 6.65 (d, J = 7.5 Hz, 1H), 5.33 (p, J = 7.1 Hz, 1H), 5.05 (ddd,J = 5.9, 3.8, 2.0 Hz, 1H), 4.04- 3.97 (m, 3H), 3.92 (td, J = 8.4, 4.3Hz, 1H), 2.55 (s, 3H), 2.53 (d, J = 1.1 Hz, 3H), 2.32-2.22 (m, 1H),2.21-2.12 (m, 1H), 1.64 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method F)Rt = 1.87 min, MS (ESIpos): m/z = 424.4 (M + H)⁺.

In analogy to the procedure described for Example 1 the followingexamples were prepared using the appropriate carboxylic acid and amineas starting materials.

Ex. Structure Name Analytical Data 31

N-[(6- Methylpyridazin- 3-yl)methyl]-3- (5-methyl-1,3- thiazol-2-yl)-5-(prop-2-yn-1- yloxy) benzamide ¹H NMR (500 MHz, CDCl₃): δ [ppm] = 8.16(t, J = 5.4 Hz, 1H), 7.93 (t, J = 1.4 Hz, 1H), 7.60 (dd, J = 2.4, 1.5Hz, 1H), 7.53-7.49 (m, 2H), 7.46 (d, J = 1.2 Hz, 1H), 7.30 (d, J = 8.6Hz, 1H), 4.87 (d, J = 5.5 Hz, 2H), 4.74 (d, J = 2.4 Hz, 2H), 2.66 (s,3H), 2.54 (t, J = 2.4 Hz, 1H), 2.47 (d, J = 1.1 Hz, 3H). LCMS(Analytical Method F) Rt = 2.51 min, MS (ESIpos): m/z = 379.1 (M + H)⁺.32

N-[(5-Chloro- 3-fluoropyridin- 2-yl)methyl]- 3-(5-methyl- 1,3-thiazol-2-yl)-5-(prop-2- yn-1-yloxy) benzamide ¹H NMR (500 MHz, CDCl₃): δ [ppm] =8.39 (d, J = 1.7 Hz, 1H), 7.98 (br s, 1H), 7.67 (dd, J = 2.4, 1.5 Hz,1H), 7.56-7.52 (m, 2H), 7.51-7.46 (m, 2H), 4.83-4.81 (m, 4H), 2.57 (t, J= 2.4 Hz, 1H), 2.53 (d, J = 1.0 Hz, 3H). LCMS (Analytical Method F) Rt =3.48 min, MS (ESIpos): m/z = 416.0 (M + H)\⁺. 33

N-[(1R)-1-(6- Methylpyridin- 3-yl)ethyl]-3- (5-methyl-1,3-thiazol-2-yl)-5- (prop-2-yn-1- yloxy) benzamide ¹H NMR (500 MHz, CDCl₃):δ [ppm] = 8.58 (d, J = 1.9 Hz, 1H), 7.87 (t, J = 1.3 Hz, 1H), 7.64 (dd,J = 8.0, 2.3 Hz, 1H), 7.59 (dd, J = 2.4, 1.4 Hz, 1H), 7.51 (d, J = 1.2Hz, 1H), 7.49 (dd, J = 2.4, 1.5 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.59(d, J = 7.0 Hz, 1H), 5.32 (p, 1H), 4.78 (d, J = 2.4 Hz, 2H), 2.56 (s,3H), 2.55 (t, J = 2.4 Hz, 1H), 2.52 (d, J = 1.1 Hz, 3H), 1.63 (d, J =7.0 Hz, 3H). LCMS (Analytical Method F) Rt = 1.99 min, MS (ESIpos): m/z= 392.1 (M + H)⁺. 34

N-[(1R)-1-(5- Methylpyrazin- 2-yl)ethyl]-3- (5-methyl-1,3-thiazol-2-yl)-5- (prop-2-yn-1- yloxy) benzamide ¹H NMR (500 MHz,Benzene-d6): δ [ppm] = 8.53 (d, J = 1.4 Hz, 1H), 8.41 (s, 1H), 7.95 (s,1H), 7.63 (dd, J = 2.4, 1.5 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.50 (dd,J = 2.4, 1.5 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 5.43 (p, J = 6.9 Hz,1H), 4.80 (d, J = 2.4 Hz, 2H), 2.57 (s, 3H), 2.56 (t, J = 2.4 Hz, 1H),2.53 (d, J = 1.1 Hz, 3H), 1.60 (d, J = 6.8 Hz, 3H). LCMS (AnalyticalMethod F) Rt = 3.00 min, MS (ESIpos): m/z = 393.1 (M + H)⁺. 35

N-[(5- Methylpyrazin- 2-yl)methyl]- 3-(5-methyl- 1,3-thiazol-2-yl)-5-(prop-2- yn-1- yloxy)benzamide ¹H NMR (500 MHz, CDCl₃): δ [ppm] =8.56 (d, J = 1.2 Hz, 1H), 8.42 (s, 1H), 7.95 (t, J = 1.4 Hz, 1H), 7.65(dd, J = 2.5, 1.5 Hz, 1H), 7.52 (dd, J = 2.4, 1.4 Hz, 2H), 7.27 (s, 1H),4.80 (d, J = 2.4 Hz, 2H), 4.78 (d, J = 5.2 Hz, 2H), 2.58 (s, 3H), 2.56(t, J = 2.4 Hz, 1H), 2.53 (d, J = 1.1 Hz, 3H). LCMS (Analytical MethodF) Rt = 2.78 min, MS (ESIpos) m/z = 379 (M + H)⁺. 36

3-(5-Methyl- 1,3-thiazol-2- yl)-5-(prop-2- yn-1-yloxy)-N- {(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide ¹H NMR (500 MHz,DMSO-d6): δ [ppm] = 9.17 (d, J = 7.1 Hz, 1H), 9.11 (s, 2H), 7.97 (t, J =1.4 Hz, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.63 (dd, J = 2.4, 1.5 Hz, 1H),7.56 (dd, J = 2.4, 1.5 Hz, 1H), 5.30 (p, J = 7.0 Hz, 1H), 4.95 (d, J =2.3 Hz, 2H), 3.62 (t, J = 2.3 Hz, 1H), 3.31 (s, 3H), 1.61 (d, J = 7.1Hz, 3H). LCMS (Analytical Method F) Rt = 3.54 min, MS (ESIpos) m/z = 447(M + H)⁺. 37

N-[(1R)-1-(6- Methylpyridazin- 3-yl)ethyl]- 3-(5-methyl- 1,3-thiazol-2-yl)-5-(prop-2- yn-1- yloxy) benzamide ¹H NMR (500 MHz, CDCl₃): δ [ppm] =7.93 (t, J = 1.4 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.65 (dd, J = 2.4,1.5 Hz, 1H), 7.53-7.48 (m, 2H), 7.39 (d, J = 8.6 Hz, 1H), 7.33 (d, J =8.6 Hz, 1H), 5.46 (p, J = 6.9 Hz, 1H), 4.79 (d, J = 2.4 Hz, 2H), 2.72(s, 3H), 2.56 (t, J = 2.4 Hz, 1H), 2.52 (d, J = 1.0 Hz, 3H), 1.68 (d, J= 6.8 Hz, 3H). LCMS (Analytical Method F) Rt = 2.64 min, MS (ESIpos) m/z= 437 (M + H)⁺. 38

3-(5-Methyl- 1,3-thiazol-2- yl)-5-(prop-2- yn-1-yloxy)-N- [(1R)-1-[6-(trifluoromethyl) pyridazin-3- yl]ethyl] benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 7.93 (t, J = 1.4 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H),7.74 (d, J = 8.7 Hz, 1H), 7.63 (dd, J = 2.4, 1.4 Hz, 1H), 7.55- 7.45 (m,3H), 5.60 (p, J = 7.0 Hz, 1H), 4.78 (d, J = 2.4 Hz, 2H), 2.56 (t, J =2.4 Hz, 1H), 2.52 (d, J = 1.1 Hz, 3H), 1.76 (d, J = 7.0 Hz, 3H). LCMS(Analytical Method D) Rt = 4.18 min, MS (ESIpos): m/z = 447 (M + H)⁺. 39

N-[(1R)-1-(2- Methylpyrimidin- 5-yl)ethyl]- 3-(5-methyl- 1,3-thiazol-2-yl)-5-(prop-2- yn-1- yloxy) benzamide ¹H NMR (500 MHz, DMSO-d6): δ [ppm]= 9.06 (d, J = 7.5 Hz, 1H), 8.72 (s, 2H), 7.95 (t, J = 1.4 Hz, 1H), 7.65(d, J = 1.2 Hz, 1H), 7.62 (dd, J = 2.4, 1.5 Hz, 1H), 7.54 (dd, J = 2.4,1.4 Hz, 1H), 5.17 (p, J = 7.1 Hz, 1H), 4.94 (d, J = 2.3 Hz, 2H), 4.03(s, 1H), 3.62 (t, J = 2.3 Hz, 1H), 3.31 (s, 3H), 2.59 (s, 3H), 1.55 (d,J = 7.1 Hz, 3H). LCMS (Analytical Method A) Rt = 1.17 min, MS (ESIpos):m/z = 393.1 (M + H)⁺.

In analogy to the procedure described for Example 7 the followingexamples were prepared using the appropriate carboxylic acid and amineas starting materials.

Ex. Structure Name Analytical Data 40

3-(But-2-yn-1- yloxy)-5-(5- methyl-1,3- thiazol-2-yl)- N-[(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl] benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.94 (s, 2H), 7.90 (t, J = 1.4 Hz, 1H), 7.58 (dd, J =2.4, 1.4 Hz, 1H), 7.55-7.51 (m, 1H), 7.48-7.44 (m, 1H), 6.66 (d, J = 7.0Hz, 1H), 5.36 (p, J = 7.0 Hz, 1H), 4.74 (q, J = 2.3 Hz, 2H), 2.54 (d, J= 1.0 Hz, 3H), 1.87 (t, J = 2.3 Hz, 3H), 1.71 (d, J = 7.0 Hz, 3H). LCMS(Analytical Method F) Rt = 3.478min, MS (ESIpos): m/z = 461.1 (M + H)⁺.41

3-(But-2-yn-1- yloxy)-N-[(1R)- 1-(5-methyl- 1,3,4- thiadiazol-2-yl)ethyl]-5-(5- methyl-1,3- thiazol-2- yl)benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 7.82 (s, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.41 (s,1H), 7.10 (d, J = 7.6 Hz, 1H), 5.61 (p, J = 7.0 Hz, 1H), 4.67 (d, J =2.2 Hz, 2H), 2.68 (s, 3H), 2.45 (s, 3H), 1.80 (t, J = 2.1 Hz, 3H), 1.72(d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt = 4.11 min, MS(ESIpos): m/z = 413 (M + H)⁺.

Example 42N-[(1R)-1-(5-Methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (81 mg, 0.28 mmol),(1R)-1-(5-methylpyrazin-2-yl)ethanamine (44 mg, 0.32 mmol), DIPEA (144mg, 1.11 mmol) and HATU (148 mg, 0.39 mmol) were dissolved in DMF (3.7mL). The reaction mixture was stirred at RT until complete conversionand evaporated to dryness. Crude material was purified by preparativeHPLC (method 1, rt: 1.00 min) to afford the title compound 20 mg (18%yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.54 (d, J=7.07 Hz, 3 H) 2.48 (s, 3 H)4.55-4.63 (m, 2 H) 4.95 (t, J=6.95 Hz, 2 H) 5.23 (s, 1 H) 5.46 (s, 1 H)7.37 (t, J=1.52 Hz, 2 H) 7.65 (d, J=1.01 Hz, 1 H) 7.98 (t, J=1.39 Hz, 1H) 8.49 (d, J=0.76 Hz, 1 H) 8.56 (d, J=1.26 Hz, 1 H) 9.10 (d, J=7.33 Hz,1 H).

Example 43N-[(1R)-1-(2-Methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (73 mg, 0.25 mmol),(1R)-1-(2-methylpyrimidin-5-yl)ethanamine dihydrochloride (58 mg, 0.28mmol), DIPEA (0.17 ml, 1.0 mmol) and HATU (133 mg, 0.35 mmol) weredissolved in DMF (3.3 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. Crude material waspurified by preparative HPLC (method 1, rt: 0.93 min) to afford thetitle compound 48 mg (47% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.55 (d, J=7.10 Hz, 3 H) 2.59 (s, 3 H)4.55-4.62 (m, 2 H) 4.91-4.99 (m, 2 H) 5.16 (t, J=7.22 Hz, 1 H) 5.41-5.50(m, 1 H) 7.31-7.40 (m, 2 H) 7.65 (d, J=1.01 Hz, 1 H) 7.95 (t, J=1.39 Hz,1 H) 8.72 (s, 2 H) 9.07 (d, J=7.35 Hz, 1 H).

Example 44N-[1-(5-Chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (74 mg, 0.25 mmol), (+/−)1-(5-chloro-3-fluoropyridin-2-yl)ethanamine (49 mg, 0.28 mmol), DIPEA(131 mg, 1.02 mmol) and HATU (136 mg, 0.36 mmol) were dissolved in DMF(3.4 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. Crude material was purified bypreparative HPLC (method 1, rt: 1.24 min) to afford the title compound50 mg (43% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.52 (d, J=7.10 Hz, 3 H) 4.54-4.62 (m,2 H) 4.95 (t, J=6.59 Hz, 2 H) 5.36-5.49 (m, 2 H) 7.33-7.39 (m, 2 H) 7.64(d, J=1.27 Hz, 1 H) 7.96 (t, J=1.39 Hz, 1 H) 8.07 (dd, J=9.89, 2.03 Hz,1 H) 8.50 (d, J=2.03 Hz, 1 H) 9.12 (d, J=7.10 Hz, 1 H).

Example 45N-[(6-Methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (73 mg, 0.25 mmol),1-(6-methylpyridazin-3-yl)methanamine (34 mg, 0.27 mmol), DIPEA (129 mg,1.0 mmol) and HATU (133 mg, 0.35 mmol) were dissolved in DMF (3.3 mL).The reaction mixture was stirred at RT until complete conversion andevaporated to dryness. Crude material was purified by preparative HPLC(method 1, rt: 0.87 min) to afford the title compound 40 mg (40% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 2.61 (s, 3 H) 4.59 (dd, J=7.86, 4.82Hz, 2 H) 4.73 (d, J=5.83 Hz, 2 H) 4.96 (t, J=6.84 Hz, 2 H) 5.40-5.50 (m,1 H) 7.36 (dd, J=2.28, 1.52 Hz, 1 H) 7.41 (dd, J=2.53, 1.52 Hz, 1 H)7.57 (s, 2 H) 7.65 (d, J=1.27 Hz, 1 H) 8.01 (t, J=1.39 Hz, 1 H) 9.41 (t,J=5.96 Hz, 1 H).

Example 46N-[(1R)-1-(5-Chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (81 mg, 0.28 mmol),(1R)-1-(5-chloropyridin-2-yl)ethanamine hydrochloride (59 mg, 0.31mmol), DIPEA (144 mg, 1.11 mmol) and HATU (148 mg, 0.39 mmol) weredissolved in DMF (3.7 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. Crude material waspurified by preparative HPLC (method 2, rt: 1.17 min) to afford thetitle compound 20 mg (17% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.52 (d, J=7.10 Hz, 3 H) 4.59 (ddd,J=7.16, 4.63, 2.66 Hz, 2 H) 4.96 (t, J=6.59 Hz, 2 H) 5.19 (t, J=7.22 Hz,1 H) 5.42-5.50 (m, 1 H) 7.36-7.41 (m, 2 H) 7.46 (d, J=8.62 Hz, 1 H) 7.65(d, J=1.27 Hz, 1 H) 7.90 (dd, J=8.62, 2.53 Hz, 1 H) 7.99 (t, J=1.39 Hz,1 H) 8.58 (d, J=2.03 Hz, 1 H) 9.09 (d, J=7.35 Hz, 1 H).

Example 47N-[(1R)-1-(6-Methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (72 mg, 0.25 mmol),(1R)-1-(6-methylpyridazin-3-yl)ethanamine hydrochloride (IntermediateXV, 47 mg, 0.27 mmol), DIPEA (128 mg, 0.99 mmol) and HATU (132 mg, 0.35mmol) were dissolved in DMF (3.3 mL). The reaction mixture was stirredat RT until complete conversion and evaporated to dryness. Crudematerial was purified by preparative HPLC (method 1, rt: 0.92 min) toafford the title compound 30 mg (30% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.59 (d, J=7.10 Hz, 3 H) 2.60 (s, 3 H)4.59 (ddd, J=7.10, 4.44, 2.91 Hz, 2 H) 4.96 (t, J=6.72 Hz, 2 H) 5.36 (t,J=7.35 Hz, 1 H) 5.46 (t, J=5.32 Hz, 1 H) 7.38 (d, J=1.52 Hz, 2 H)7.51-7.56 (m, 1 H) 7.57-7.62 (m, 1 H) 7.65 (d, J=1.01 Hz, 1 H) 7.99 (t,J=1.27 Hz, 1 H) 9.16 (d, J=7.60 Hz, 1 H).

Example 483-(5-Methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5F (76 mg, 0.26 mmol), Intermediate VI (65 mg, 0.29 mmol),DIPEA (135 mg, 1.04 mmol) and HATU (139 mg, 0.36 mmol) were dissolved inDMF (3.5 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. Crude material was purified bycolumn chromatography (silica, gel, hexane/EE gradient) to afford thetitle compound 80 mg (65% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, J=7.10 Hz, 3 H) 4.54-4.62 (m,2 H) 4.96 (t, J=6.59 Hz, 2 H) 5.29 (s, 1 H) 5.46 (t, J=4.94 Hz, 1 H)7.37 (d, J=1.01 Hz, 2 H) 7.65 (d, J=1.01 Hz, 1 H) 7.96 (t, J=1.39 Hz, 1H) 9.12 (s, 2 H) 9.18 (d, J=7.10 Hz, 1 H).

Example 49N-[1-(3-Chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (79 mg, 0.27 mmol), (+/−)1-(3-chloro-5-fluoropyridin-2-yl)ethanamine (52 mg, 0.30 mmol), DIPEA(140 mg, 1.08 mmol) and HATU (144 mg, 0.38 mmol) were dissolved in DMF(3.6 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. Crude material was purified bypreparative HPLC (method 1, rt: 1.24 min) to afford the title compound60 mg (50% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.49 (d, J=7.07 Hz, 3 H) 4.54-4.62 (m,2 H) 4.95 (t, J=6.82 Hz, 2 H) 5.41-5.48 (m, 1 H) 5.53 (t, J=7.07 Hz, 1H) 7.33-7.39 (m, 2 H) 7.64 (d, J=1.26 Hz, 1 H) 7.97 (t, J=1.52 Hz, 1 H)8.09 (dd, J=8.59, 2.53 Hz, 1 H) 8.58 (d, J=2.78 Hz, 1 H) 9.09 (d, J=7.07Hz, 1 H).

Example 50N-[(1R)-1-(5-Methyl-1,3,4-thiadiazol-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

3-(5-Methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzoic acid (58.3 mg,0.2 mmol), (1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethanaminehydrochloride (43 mg, 0.24 mmol) and DIPEA (0.174 mL, 1.0 mmol) weredissolved in DCM (2 mL). T3P (0.23 mL, 0.4 mmol, 50% solution in EtOAc)was added and the reaction mixture stirred at RT for 2 h. The reactionmixture washed with 2 M NaOH (2 mL) and the aqueous layer furtherextracted with DCM (2×2 mL). The crude material was purified by BiotageIsolera™ chromatography on silica gel (eluent: heptane-acetone, 0 to1:1) to give 44.7 mg (54% yield) of the title compound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=7.87 (t, J=1.3 Hz, 1H), 7.52 (d,J=1.1 Hz, 1H), 7.40 (dd, J=2.4, 1.4 Hz, 1H), 7.22 (dd, J=2.3, 1.5 Hz,1H), 7.08 (d, J=7.5 Hz, 1H), 5.68 (p, J=7.0 Hz, 1H), 5.33 (p, J=5.5 Hz,1H), 5.06-5.01 (m, 2H), 4.78 (dd, J=7.4, 5.4 Hz, 2H), 2.77 (s, 3H), 2.53(d, J=1.1 Hz, 3H), 1.79 (d, J=6.9 Hz, 3H).

LCMS (Analytical Method D) Rt=3.61 min, MS (ESIpos): m/z=417 (M+H)⁺.

Example 51N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

3-(5-Methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzoic acid (210 mg,0.72 mmol), (1R)-1-(6-methylpyridin-3-yl)ethanamine (37 mg, 0.27 mmol),DIPEA (191 μL, 1.1 mmol) and HATU (125 mg, 0.33 mmol) were dissolved inDCM (1 mL) and stirred at RT for 2 h. The reaction mixture was dilutedwith DCM (1 mL), washed with water (1 mL), dried (over Na₂SO₄) andconcentrated in vacuo. The crude material was purified twice bypreparative HPLC (Method A) to give 16.8 mg (6% yield) of the titlecompound as a white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.55 (d, J=2.3 Hz, 1H), 7.83 (t,J=1.3 Hz, 1H), 7.59 (dd, J=8.0, 2.4 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H),7.36 (dd, J=2.4, 1.4 Hz, 1H), 7.21-7.11 (m, 2H), 6.48 (d, J=7.5 Hz, 1H),5.36-5.26 (m, 2H), 5.02 (t, J=7.0 Hz, 2H), 4.76 (t, J=5.8 Hz, 2H), 2.54(s, 3H), 2.53 (d, J=1.1 Hz, 3H), 1.63 (d, J=7.0 Hz, 3H).

LCMS (Analytical Method F) Rt=1.76 min, MS (ESIpos): m/z=409 (M+H)⁺.

In analogy to the procedure described for Example 1 the followingexample was prepared using the appropriate carboxylic acid and amine asstarting materials.

Ex. Structure Name Analytical Data 52

3-(5-Methyl- 1,3-thiazol-2- yl)-5-(oxetan- 3-yloxy)-N-{[6-(trifluoromethyl) pyridazin-3- yl]methyl} benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 7.91 (t, J = 1.3 Hz, 1H), 7.82 (s, 2H), 7.66 (t, J =5.2 Hz, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.39 (dd, J = 2.3, 1.4 Hz, 1H),7.23 (dd, J = 2.3, 1.5 Hz, 1H), 5.32 (p, J = 5.5 Hz, 1H), 5.06- 4.99 (m,4H), 4.77 (dd, J = 7.7, 5.1 Hz, 2H), 2.52 (d, J = 1.0 Hz, 3H). LCMS(Analytical Method D) Rt = 3.97, MS (ESIpos) m/z = 451 (M + H)⁺.

In analogy to the procedure described for Example 7 the followingexample was prepared using the appropriate carboxylic acid and amine asstarting materials.

Ex. Structure Name Analytical Data 53

3-(5-Methyl- 1,3-thiazol-2- yl)-5-(oxetan- 3-yloxy)-N- [(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]propyl] benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.91 (s, 2H), 7.87 (s, 1H), 7.53 (d, J = 1.1 Hz, 1H),7.38 (dd, J = 2.3, 1.4 Hz, 1H), 7.18-7.14 (m, 1H), 6.61 (d, J = 6.9 Hz,1H), 5.31 (p, J = 5.5 Hz, 1H), 5.09 (q, J = 7.1 Hz, 1H), 5.05-5.00 (m,2H), 4.77 (dd, J = 7.4, 5.2 Hz, 2H), 2.54 (d, J = 1.0 Hz, 3H), 2.12-1.97(m, 2H), 1.08 (t, J = 7.4 Hz, 3H). LCMS (Analytical Method F) Rt = 3.48min, MS (ESIpos): m/z = 479 (M + H)⁺.

Example 54N-[(6-Methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

A mixture of3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid (100 mg, 0.313 mmol), (6-methylpyridazin-3-yl)methanamine (46 mg,0.376 mmol), HATU (142 mg, 0.376 mmol) and DIPEA (60 mg, 0.47 mmol) inDCM (4 mL) were stirred at RT for 4 h. The solvent was removed in vacuoand the residue purified by Biotage Isolera™ chromatography (silica,eluting with 100% EtOAc followed by 1-6% MeOH in DCM) to give 110 mg(79% yield) of the title compound as an off-white gum.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 7.89 (t, J=1.4 Hz, 1H), 7.76 (s, 1H),7.63-7.55 (m, 1H), 7.50-7.42 (m, 3H), 7.31 (d, J=8.6 Hz, 1H), 4.89 (d,J=5.3 Hz, 2H), 4.29 (qd, J=6.8, 4.3 Hz, 1H), 4.04 (h, J=5.8 Hz, 2H),3.97-3.88 (m, 1H), 3.87-3.79 (m, 1H), 2.69 (s, 3H), 2.50 (d, J=0.9 Hz,3H), 2.07 (dtd, J=12.4, 7.6, 5.5 Hz, 1H), 2.01-1.91 (m, 2H), 1.76 (dq,J=12.2, 7.0 Hz, 1H).

LCMS (Analytical Method F) Rt=2.53 min, MS (ESIpos): m/z=424 (M+H)+.

Example 55N-[(5-Chloro-3-fluoropyridin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

A mixture of3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid (100 mg, 0.313 mmol), (5-chloro-3-fluoropyridin-2-yl)methanaminehydrochloride (74 mg, 0.376 mmol), HATU (143 mg, 0.376 mmol) and DIPEA(101 mg, 0.783 mmol) in DCM (4 mL) was stirred at RT for 3 h. Thesolvent was removed in vacuo and the residue purified by preparativeHPLC (Method A) to give 95.2 mg (64% yield) of the title compound as anoff-white solid.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.39 (d, J=1.7 Hz, 1H), 7.92 (t, J=1.4Hz, 1H), 7.63 (dd, J=2.4, 1.5 Hz, 1H), 7.56-7.41 (m, 4H), 4.81 (dd,J=4.7, 1.7 Hz, 2H), 4.32 (qd, J=7.0, 3.9 Hz, 1H), 4.13-4.04 (m, 2H),3.95 (dt, J=8.2, 6.7 Hz, 1H), 3.89-3.83 (m, 1H), 2.53 (d, J=1.1 Hz, 3H),2.14-2.06 (m, 1H), 2.03-1.91 (m, 2H), 1.77 (ddt, J=12.2, 8.4, 7.1 Hz,1H).

LCMS (Analytical Method F) Rt=3.53 min, MS (ESIpos): m/z=461 (M+H)+.

Example 56N-[(5-Methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

To a stirred solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid (49 mg, 0.15 mmol), 1-(5-methylpyrazin-2-yl)methanaminehydrochloride (26.9 mg, 0.169 mmol), DIPEA (0.107 μL, 0.614 mmol) andDMAP (3.7 mg, 0.03 mmol) in DCM (2 mL) was added HATU (70.0 mg, 0.184mmol) and the reaction stirred for 1.5 h at RT. The reaction mixture wasdiluted with water (3 mL) and the aqueous layer re-extracted withfurther DCM (2×3 mL). The combined organics were dried (over MgSO₄) andconcentrated under reduced pressure. The crude material was purified bypreparative HPLC (Method A) to give 39.8 mg (61% yield) of the titlecompound as a colourless glass.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.55 (d, J=1.2 Hz, 1H), 8.42 (s, 1H),7.90 (t, J=1.4 Hz, 1H), 7.61 (dd, J=2.4, 1.5 Hz, 1H), 7.51 (d, J=1.2 Hz,1H), 7.47 (dd, J=2.4, 1.5 Hz, 1H), 7.25-7.21 (m, 1H), 4.77 (d, J=5.2 Hz,2H), 4.31 (qd, J=6.9, 3.9 Hz, 1H), 4.11 (dd, J=9.7, 3.9 Hz, 1H), 4.06(dd, J=9.7, 6.5 Hz, 1H), 3.95 (dt, J=8.2, 6.7 Hz, 1H), 3.88-3.82 (m,1H), 2.58 (s, 3H), 2.52 (d, J=1.1 Hz, 3H), 2.15-2.05 (m, 1H), 2.03-1.90(m, 2H), 1.82-1.72 (m, 1H).

LCMS (Analytical Method D) Rt=3.79 min, MS (ESIpos): m/z=425.1 (M⁺H)+.

Example 57N-[(1R)-1-(5-Methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

To a stirred solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid (49 mg, 0.15 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanaminehydrochloride (29.3 mg, 0.169 mmol), DIPEA (0.107 μL, 0.614 mmol) andDMAP (3.7 mg, 0.03 mmol) in DCM (2 mL) was added HATU (70.0 mg, 0.184mmol) and the reaction stirred for 1.5 h at RT. The reaction mixture wasdiluted with water (3 mL) and the aqueous layer re-extracted withfurther DCM (2×3 mL). The combined organics were dried (over MgSO₄) andconcentrated under reduced pressure. The crude material was purified bypreparative HPLC (Method A) to give 29.7 mg (44% yield) of the titlecompound as an orange glass.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.53 (d, J=1.3 Hz, 1H), 8.41 (s, 1H),7.90 (s, 1H), 7.60 (dd, J=2.4, 1.5 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.45(dd, J=2.4, 1.5 Hz, 1H), 7.31 (d, J=7.4 Hz, 1H), 5.42 (p, J=6.9 Hz, 1H),4.31 (qd, J=7.0, 3.9 Hz, 1H), 4.10 (dd, J=9.7, 3.8 Hz, 1H), 4.05 (dd,J=9.7, 6.6 Hz, 1H), 3.95 (dt, J=8.3, 6.7 Hz, 1H), 3.88-3.83 (m, 1H),2.57 (s, 3H), 2.53 (d, J=1.1 Hz, 3H), 2.09 (dtd, J=12.4, 7.7, 7.2, 5.5Hz, 1H), 1.97 (tq, J=15.8, 6.0, 5.2 Hz, 2H), 1.76 (ddd, J=15.6, 12.3,7.1 Hz, 1H), 1.60 (d, J=6.8 Hz, 3H).

LCMS (Analytical Method F) Rt=3.96 min, MS (ESIpos): m/z=439.1 (M+H)+.

Example 583-(5-Methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a stirred solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid (49 mg, 0.15 mmol), Intermediate VI (38.4 mg, 0.169 mmol), DIPEA(0.107 μL, 0.614 mmol) and DMAP (3.7 mg, 0.03 mmol) in DCM (2 mL) wasadded HATU (70.0 mg, 0.184 mmol) and the reaction stirred for 1.5 h atRT. The reaction mixture was diluted with water (3 mL) and the aqueouslayer re-extracted with further DCM (2×3 mL). The combined organics weredried (over MgSO₄) and concentrated under reduced pressure. The crudematerial was purified preparative HPLC (Method A). The material wasfurther purified by trituration from acetonitrile to give 17.5 mg (23%yield) of the title compound as a white powder.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.94 (s, 2H), 7.89 (s, 1H), 7.56 (dd,J=2.4, 1.5 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.41 (dd, J=2.3, 1.5 Hz,1H), 6.71 (d, J=6.6 Hz, 1H), 5.35 (p, J=7.0 Hz, 1H), 4.30 (qd, J=7.0,3.7 Hz, 1H), 4.09 (dd, J=9.7, 3.7 Hz, 1H), 4.02 (dd, J=9.7, 6.6 Hz, 1H),3.97-3.92 (m, 1H), 3.88-3.82 (m, 1H), 2.53 (d, J=1.1 Hz, 3H), 2.09 (dtd,J=12.3, 7.6, 7.2, 5.4 Hz, 1H), 1.97 (qt, J=12.1, 5.8 Hz, 2H), 1.79-1.74(m, 1H), 1.72 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method F) Rt=3.59 min, MS (ESIpos): m/z=493.1 (M+H)+.

Example 59N-[(1R)-1-(6-Methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

To a stirred solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid (49 mg, 0.15 mmol), (1R)-1-(6-methylpyridazin-3-yl)ethanaminehydrochloride (29.3 mg, 0.169 mmol), DIPEA (0.107 μL, 0.614 mmol) andDMAP (3.7 mg, 0.03 mmol) in DCM (2 mL) was added HATU (70.0 mg, 0.184mmol) and the reaction stirred for 1.5 h at RT. The reaction mixture wasdiluted with water (3 mL) and the aqueous layer re-extracted withfurther DCM (2×3 mL). The combined organics were dried (over MgSO₄) andconcentrated under reduced pressure. The crude material was purified bypreparative HPLC (Method A). The material was further purified bytrituration from acetonitrile to give 31.9 mg (47% yield) of the titlecompound as a white powder.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 7.90 (s, 1H), 7.71 (d, J=7.2 Hz, 1H),7.63-7.60 (m, 1H), 7.51 (d, J=1.0 Hz, 1H), 7.46-7.43 (m, 1H), 7.40 (d,J=8.6 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 5.46 (p, J=6.9 Hz, 1H), 4.35-4.26(m, 1H), 4.08 (qd, J=9.7, 5.2 Hz, 2H), 4.00-3.91 (m, 1H), 3.88-3.79 (m,1H), 2.72 (s, 3H), 2.52 (d, J=0.8 Hz, 3H), 2.15-2.05 (m, 1H), 1.97 (qt,J=12.3, 6.7 Hz, 2H), 1.85-1.74 (m, 1H), 1.68 (d, J=6.8 Hz, 3H).

LCMS (Analytical Method F) Rt=2.67 min, MS (ESIpos): m/z=439.1 (M+H)⁺.

Example 603-(5-Methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

To a stirred solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoicacid (50 mg, 0.157 mmol),(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethanamine hydrochloride (39mg, 0.171 mmol) and DIPEA (109 μL, 0.626 mmol) in DCM (1 mL) was addedHATU (71 mg, 0.187 mmol) and the reaction mixture stirred at RT for 2 h.The mixture was diluted with DCM (1 mL) and washed with water (2×2 mL).The aqueous phase was re-extracted with DCM (2 mL) and the combinedorganics dried (over Na₂SO₄) and concentrated in vacuo. The crudematerial was purified by preparative HPLC (Method A) to give 34.7 mg(45% yield) of the title compound as a white powder.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 7.83 (s, 1H), 7.75 (d, J=8.7 Hz, 1H),7.67 (d, J=8.7 Hz, 1H), 7.53 (dd, J=2.4, 1.5 Hz, 1H), 7.45 (d, J=1.2 Hz,1H), 7.42-7.34 (m, 2H), 5.53 (p, J=7.0 Hz, 1H), 4.23 (qd, J=6.9, 4.0 Hz,1H), 4.05-3.94 (m, 2H), 3.92-3.83 (m, 1H), 3.82-3.74 (m, 1H), 2.45 (d,J=1.1 Hz, 3H), 2.07-1.97 (m, 1H), 1.93-1.84 (m, 2H), 1.76-1.65 (m, 4H).

LCMS (Analytical Method F) Rt=3.50 min, MS (ESIpos): m/z=493.1 (M+H)+.

Example 61N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[[(2R)-tetrahydrofuran-2-yl]methoxy]benzoicacid (40 mg, 0.125 mmol), (1R)-1-(6-methylpyridazin-3-yl)ethanaminehydrochloride (29 mg, 0.167 mmol) and DIPEA (87 μL, 0.499 mmol) in DCM(2 mL) was added HATU (60 mg, 0.158 mmol). The reaction mixture wasstirred for 1 h at RT then diluted with DCM (10 mL) and water (10 mL).The aqueous layer was re-extracted with DCM (10 mL) and the combinedorganic layers dried (over Na₂SO₄) and concentrated under reducedpressure. The crude material was purified by preparative HPLC (Method A)to give 45 mg (78% yield) of the title compound as a white foam.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 7.88 (s, 1H), 7.76 (d, J=7.3 Hz, 1H),7.62-7.57 (m, 1H), 7.48 (s, 1H), 7.45-7.41 (m, 1H), 7.39 (d, J=8.6 Hz,1H), 7.31 (d, J=8.6 Hz, 1H), 5.49-5.40 (m, 1H), 4.32-4.24 (m, 1H),4.09-4.00 (m, 2H), 3.96-3.89 (m, 1H), 3.86-3.78 (m, 1H), 2.70 (s, 3H),2.50 (s, 3H), 2.13-2.03 (m, 1H), 2.02-1.86 (m, 2H), 1.82-1.71 (m, 1H),1.66 (d, J=6.9 Hz, 3H).

LCMS (Analytical Method D) Rt=3.66 min, MS (ESIpos): m/z=439.1 (M+H)+.

Example 62N-[(6-Methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[[(2R)-tetrahydrofuran-2-yl]methoxy]benzoicacid (40 mg, 0.125 mmol), 1-(6-methylpyridazin-3-yl)methanamine (25 mg,0.203 mmol) and DIPEA (87 μL, 0.499 mmol) in DCM (2 mL) was added HATU(60 mg, 0.158 mmol). The reaction was stirred for 16 hours at RT thendiluted with DCM (10 mL) and water (10 mL). The aqueous layer wasre-extracted with DCM (10 mL) and the combined organic layers were dried(over Na₂SO₄) and concentrated under reduced pressure. The crudematerial was purified by preparative HPLC (Method A) to give 44 mg (79%yield) of the title compound as a yellow solid.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 7.89 (s, 1H), 7.71 (t, J=5.0 Hz, 1H),7.62-7.58 (m, 1H), 7.51-7.43 (m, 3H), 7.31 (d, J=8.6 Hz, 1H), 4.90 (d,J=5.3 Hz, 2H), 4.34-4.23 (m, 1H), 4.09-4.01 (m, 2H), 3.96-3.90 (m, 1H),3.87-3.80 (m, 1H), 2.70 (s, 3H), 2.50 (s, 3H), 2.13-2.03 (m, 1H),2.03-1.88 (m, 2H), 1.85-1.72 (m, 1H).

LCMS (Analytical Method F) Rt=2.55 min, MS (ESIpos): m/z=425.2 (M+H)+.

Example 633-(5-Methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[[(2R)-tetrahydrofuran-2-yl]methoxy]benzoicacid (40 mg, 0.125 mmol), Intermediate VI (33 mg, 0.190 mmol) and DIPEA(87 μL, 0.499 mmol) in DCM (2 mL) was added HATU (60 mg, 0.158 mmol).The reaction was stirred for 1 h at RT then diluted with DCM (10 mL) andwater (10 mL). The aqueous layer was re-extracted with DCM (10 mL) andthe combined organic layers dried (over Na₂SO₄) and concentrated underreduced pressure. The crude material was purified by preparative HPLC(Method A) to give 42 mg (65% yield) of the title compound as a whitesolid.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.93 (s, 2H), 7.81 (s, 1H), 7.48 (s,2H), 7.30 (s, 1H), 6.95 (s, 1H), 5.40-5.27 (m, 1H), 4.33-4.23 (m, 1H),4.07-3.90 (m, 3H), 3.90-3.81 (m, 1H), 2.51 (s, 3H), 2.13-2.03 (m, 1H),2.03-1.89 (m, J=7.3, 6.6 Hz, 2H), 1.76-1.64 (m, 4H).

LCMS (Analytical Method F) Rt=3.60 min, MS (ESIpos): m/z=493.1 (M+H)+.

Example 64N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

To a solution of3-(5-methyl-1,3-thiazol-2-yl)-5-[[(2R)-tetrahydrofuran-2-yl]methoxy]benzoicacid (40 mg, 0.125 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanaminehydrochloride (33 mg, 0.190 mmol) and DIPEA (87 μL, 0.499 mmol) in DCM(2 mL) was added HATU (60 mg, 0.158 mmol). The reaction was stirred for1 h at RT then diluted with DCM (10 mL) and water (10 mL). The aqueouslayer was re-extracted with DCM (10 mL) and the combined organic layersdried (over Na₂SO₄) and concentrated under reduced pressure. The crudematerial was purified by preparative HPLC (Method A) to give 49 mg (85%yield) of the title compound as a beige solid.

¹H NMR (500 MHz, CDCl₃) δ 8.52 (s, 1H), 8.40 (s, 1H), 7.90-7.84 (m, 1H),7.62-7.56 (m, 1H), 7.50 (s, 1H), 7.46-7.41 (m, 1H), 7.30 (d, J=7.0 Hz,1H), 5.42 (p, J=6.9 Hz, 1H), 4.38-4.22 (m, 1H), 4.11-4.01 (m, 2H),3.98-3.91 (m, 1H), 3.88-3.81 (m, 1H), 2.56 (s, 3H), 2.51 (s, 3H),2.14-2.04 (m, 1H), 2.03-1.88 (m, 2H), 1.81-1.69 (m, 1H), 1.59 (d, J=6.8Hz, 3H).

LCMS (Analytical Method F) Rt=3.03 min, MS (ESIpos): m/z=439.1 (M+H)+.

In analogy to the procedure described for Example 1 the followingexamples were prepared using the appropriate carboxylic acid and amineas starting materials.

Ex. Structure Name Analytical Data 65

N-[1-(5- Chloro-3- fluoropyridin- 2-yl)ethyl]-3- (5-methyL-1,3-thiazol-2- yl)-5-[(3S)- tetrahydrofuran- 3-ylmethoxy] benzamide ¹HNMR (500 MHz, CDCl₃): δ [ppm] = 8.38 (d, J = 1.8 Hz, 1H), 7.89 (t, J =1.3 Hz, 1H), 7.58 (dd, J = 2.3, 1.5 Hz, 1H), 7.57-7.51 (m, 2H), 7.47(dd, J = 8.9, 2.0 Hz, 1H), 7.42 (dd, J = 2.3, 1.5 Hz, 1H), 5.66 (p, J =6.7 Hz, 1H), 4.06 (ddd, J = 9.0, 6.4, 2.7 Hz, 1H), 4.00 (td, J = 8.9,8.4, 3.7 Hz, 1H), 3.97 3.88 (m, 2H), 3.83-3.77 (m, 1H), 3.72 (dd, J =8.1, 5.4 Hz, 1H), 2.77 (dt, J = 14.1, 7.5 Hz, 1H), 2.54 (d, J = 1.1 Hz,3H), 2.13 (dtd, J = 13.4, 8.1, 5.6 Hz, 1H), 1.76 (td, J = 12.7, 6.9 Hz,1H), 1.56 (d, J = 6.8 Hz, 3H). LCMS (Analytical Method F) Rt = 3.79 min,MS (ESIpos): m/z = 476.1 (M + H)⁺. 66

N-[(6- Methylpyridazin- 3-yl)methyl]-3- (5-methyl- 1,3-thiazol-2-yl)-5-[(3S)- tetrahydrofuran- 3-ylmethoxy] benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 7.92 (t, J = 1.4 Hz, 1H), 7.68 (s, 1H), 7.63 (dd, J =2.4, 1.5 Hz, 1H), 7.55- 7.51 (m, 2H), 7.46 (dd, J = 2.4, 1.5 Hz, 1H),7.40 (d, J = 8.6 Hz, 1H), 4.95 (d, J = 5.2 Hz, 2H), 4.08 (dd, J = 8.9,6.5 Hz, 1H), 4.05-4.00 (m, 1H), 3.99- 3.90 (m, 2H), 3.86-3.79 (m, 1H),3.74 (dd, J = 8.9, 5.4 Hz, 1H), 2.83- 2.77 (m, 1H), 2.76 (s, 3H), 2.55(d, J = 1.1 Hz, 3H), 2.20-2.12 (m, 1H), 1.78 (td, J = 12.7, 6.9 Hz, 1H).LCMS (Analytical Method F) Rt = 2.50 min, MS (ESIpos): m/z = 425.1 (M +H)⁺. 67

N-[(5- Methylpyrazin- 2-yl)methyl]-3- (5-methyl- 1,3-thiazol-2-yl)-5-[(3S)- tetrahydrofuran- 3-ylmethoxy] benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.56 (d, J = 1.2 Hz, 1H), 8.42 (s, 1H), 7.88 (t, J =1.4 Hz, 1H), 7.58 (dd, J = 2.4, 1.5 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H),7.43 (dd, J = 2.4, 1.5 Hz, 1H), 7.22 (s, 1H), 4.78 (d, J = 5.2 Hz, 2H),4.06 (dd, J = 9.0, 6.4 Hz, 1H), 4.03- 3.96 (m, 1H), 3.96-3.85 (m, 2H),3.85-3.76 (m, 1H), 3.72 (dd, J = 8.9, 5.3 Hz, 1H), 2.77 (dt, J = 14.3,7.5 Hz, 1H), 2.58 (s, 3H), 2.53 (d, J = 1.1 Hz, 3H), 2.20 2.07 (m, 1H),1.75 (td, J = 12.7, 6.9 Hz, 1H). LCMS (Analytical Method F) Rt = 2.77min, MS (ESIpos): m/z = 425.1 (M + H)⁺. 68

N-[(1R)-1-(5- Methylpyrazin- 2-yl)ethyl]- 3-(5-methyl- 1,3-thiazol-2-yl)-5-[(3S)- tetrahydrofuran- 3-ylmethoxy] benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.56 (d, J = 1.3 Hz, 1H), 8.44 (s, 1H), 7.91 (s, 1H),7.59 (dd, J = 2.3, 1.5 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.46- 7.41 (m,1H), 7.33 (d, J = 7.5 Hz, 1H), 5.46 (p, J = 7.0 Hz, 1H), 4.08 (dd, J =9.0, 6.4 Hz, 1H), 4.02 (dd, J = 10.3, 6.6 Hz, 1H), 3.98-3.90 (m, 2H),3.82 (q, J = 7.8 Hz, 1H), 3.74 (dd, J = 8.9, 5.3 Hz, 1H), 2.79 (dt, J =14.6, 7.6 Hz, 1H), 2.60 (s, 3H), 2.56 (d, J = 1.1 Hz, 3H), 2.15 (dtd, J= 13.6, 8.2, 5.6 Hz, 1H), 1.78 (td, J = 12.7, 6.9 Hz, 1H), 1.63 (d, J =6.8 Hz, 3H). LCMS (Analytical Method F) Rt = 2.99 min, MS (ESIpos): m/z= 439.2 (M + H)⁺. 69

N-[1-(3- Chloro-5- fluoropyridin- 2-yl)ethyl]-3- (5-methyl-1,3-thiazol-2- yl)-5-[(3R)- tetrahydrofuran- 3-ylmethoxy] benzamide ¹HNMR (500 MHz, CDCl₃): δ [ppm] = 8.39 (d, J = 2.5 Hz, 1H), 7.88 (t, J =1.4 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.58 (dd, J = 2.3, 1.5 Hz, 1H),7.54- 7.49 (m, 2H), 7.43 (dd, J = 2.4, 1.5 Hz, 1H), 5.76 (p, J = 6.8 Hz,1H), 4.06 (ddd, J = 9.4, 6.4, 3.1 Hz, 1H), 4.00 (td, J = 8.9, 8.4, 4.3Hz, 1H), 3.97- 3.88 (m, 2H), 3.84-3.77 (m, 1H), 3.72 (dd, J = 7.8, 5.3Hz, 1H), 2.77 (dt, J = 14.3, 7.3 Hz, 1H), 2.53 (d, J = 1.1 Hz, 3H), 2.13(dtd, J = 13.4, 8.2, 5.7 Hz, 1H), 1.76 (dq, J = 12.7, 6.8 Hz, 1H), 1.54(d, J = 6.8 Hz, 3H). LCMS (Analytical Method F) Rt_(t) = 3.79 min, MS(ESIpos): m/z = 476.1 (M + H)⁺. 70

3-(5-Methyl- 1,3-thiazol-2- yl)-5-[(3S)- tetrahydrofuran- 3-ylmethoxy]-N-[(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl] benzamide ¹H NMR(500 MHz, CDCl₃): δ [ppm] = 8.91 (s, 2H), 7.81 (s, 1H), 7.53-7.43 (m,2H), 7.34 (s, 1H), 6.91 (s, 1H), 5.34 (p, J = 7.0 Hz, 1H), 3.99 (dd, J =8.6, 6.6 Hz, 1H), 3.96-3.84 (m, 3H), 3.77 (q, J = 7.8 Hz, 1H), 3.68 (dd,J = 8.9, 5.2 Hz, 1H), 2.73 (dt, J = 14.0, 7.4 Hz, 1H), 2.51 (s, 3H),2.10 (dtd, J = 13.6, 8.1, 5.6 Hz, 1H), 1.72 (dd, J = 13.0, 7.1 Hz, 1H),1.68 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 3.55 min, MS(ESIpos): m/z = 493.1 (M + H )⁺. 71

N-[(1R)-1-(6- Methylpyridazin- 3-yl)ethyl]-3- (5-methyl- 1,3-thiazol-2-yl)-5-[(3S)- tetrahydrofuran- 3-ylmethoxy] benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 7.90 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.62-7.57 (m,1H), 7.52 (s, 1H), 7.48- 7.40 (m, 2H), 7.37 (d, J = 8.6 Hz, 1H), 5.47(p, J = 6.9 Hz, 1H), 4.08- 3.86 (m, 4H), 3.80 (q, J = 7.8 Hz, 1H), 3.71(dd, J = 8.9, 5.4 Hz, 1H), 2.74 (s, 4H), 2.53 (s, 3H), 2.13 (dtd, J =13.5, 8.1, 5.6 Hz, 1H), 1.80-1.66 (m, 4H). LCMS (Analytical Method D) Rt= 3.55 min, MS (ESIpos): m/z = 439 (M + H)⁺. 72

3-(5-Methyl- 1,3-thiazol-2- yl)-5-[(3S)- tetrahydrofuran- 3-ylmethoxy]-N-[(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl] benzamide ¹H NMR(500 MHz, CDCl₃): δ [ppm] = 7.89 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.74(d, J = 8.7 Hz, 1H), 7.58 (dd, J = 2.3, 1.5 Hz, 1H), 7.52 (d, J = 1.1Hz, 2H), 7.48 (t, J = 6.3 Hz, 1H), 7.42- 7.37 (m, 1H), 5.61 (p, J = 7.0Hz, 1H), 4.07-3.86 (m, 4H), 3.84-3.75 (m, 1H), 3.72 (dd, J = 8.9, 5.3Hz, 1H), 2.76 (dq, J = 13.6, 6.9, 6.5 Hz, 1H), 2.53 (d, J = 1.0 Hz, 3H),2.19-2.08 (m, 1H), 1.80-1.70 (m, 4H). LCMS (Analytical Method F) Rt =3.46 min, MS (ESIpos): m/z = 493.1 (M + H)⁺. 73

3-(5-Methyl- 1,3-thiazol-2- yl)-5-[(3R)- tetrahydrofuran- 3-ylmethoxy]-N-[(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl] benzamide ¹H NMR(500 MHz, CDCl₃): δ [ppm] = 8.93 (s, 2H), 7.85 (d, J = 1.2 Hz, 1H),7.54-7.48 (m, 2H), 7.40-7.35 (m, 1H), 6.75 (d, J = 6.6 Hz, 1H), 5.36 (p,J = 7.0 Hz, 1H), 4.06-3.85 (m, 4H), 3.79 (q, J = 7.8 Hz, 1H), 3.70 (dd,J = 8.9, 5.2 Hz, 1H), 2.75 (hept, J = 6.1 Hz, 1H), 2.53 (d, J = 1.0 Hz,3H), 2.12 (dtd, J = 13.4, 8.1, 5.5 Hz, 1H), 1.84 (d, J = 7.2 Hz, OH),1.79-1.68 (m, 4H). LCMS (Analytical Method D) Rt = 4.34 min, MS(ESIpos): m/z = 493 (M + H)⁺. 74

N-[(1R)-1-(5- Methylpyrazin- 2-yl)ethyl]- 3-(5-methyl- 1,3-thiazol-2-yl)-5-[(3R)- tetrahydrofuran- 3-ylmethoxy] benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.53 (d, J = 1.3 Hz, 1H), 8.41 (s, 1H), 7.87 (s, 1H),7.59-7.50 (m, 2H), 7.44- 7.38 (m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 5.43(p, J = 6.9 Hz, 1H), 4.09- 3.86 (m, 4H), 3.79 (q, J = 7.8 Hz, 1H), 3.71(dd, J = 8.9, 5.3 Hz, 1H), 2.76 (hept, J = 6.4 Hz, 1H), 2.57 (s, 3H),2.53 (d, J = 1.0 Hz, 3H), 2.12 (dtd, J = 13.5, 8.1, 5.6 Hz, 1H),1.80-1.69 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H). LCMS (Analytical Method D)Rt = 3.95 min, MS (ESIpos): m/z = 439 (M + H)⁺. 75

N-[(6- Methylpyridazin- 3-yl)methyl]-3- (5-methyl- 1,3-thiazol-2-yl)-5-[(3R)- tetrahydrofuran- 3-ylmethoxy] benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 7.96 (t, J = 5.0 Hz, 1H), 7.94-7.92 (m, 1H), 7.65-7.60(m, 2H), 7.53 (d, J = 1.2 Hz, 1H), 7.49 (dd, J = 2.3, 1.5 Hz, 1H),7.47-7.43 (m, 1H), 4.96 (d, J = 5.2 Hz, 2H), 4.12-3.88 (m, 4H),3.85-3.78 (m, 1H), 3.73 (dd, J = 8.9, 5.4 Hz, 1H), 2.83-2.75 (m, 4H),2.54 (d, J = 1.0 Hz, 3H), 2.20-2.10 (m, 1H), 1.82-1.73 (m, 1H). LCMS(Analytical Method D) Rt = 3.60 min, MS (ESIpos): m/z = 425 (M + H)⁺. 76

N-[(5- Methylpyrazin- 2-yl)methyl]-3- (5-methyl- 1,3-thiazol-2-yl)-5-[(3R)- tetrahydrofuran- 3-ylmethoxy] benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.56 (d, J = 1.1 Hz, 1H), 8.41 (s, 1H), 7.89 (s, 1H),7.57 (dd, J = 2.4, 1.5 Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.43 (dd, J =2.3, 1.5 Hz, 1H), 7.30 (t, J = 5.1 Hz, 1H), 4.77 (d, J = 5.1 Hz, 2H),4.08-3.86 (m, 4H), 3.83-3.75 (m, 1H), 3.71 (dd, J = 8.9, 5.3 Hz, 1H),2.76 (hept, J = 6.2 Hz, 1H), 2.57 (s, 3H), 2.52 (d, J = 1.1 Hz, 3H),2.12 (dtd, J = 13.3, 8.1, 5.6 Hz, 1H), 1.80- 1.69 (m, 1H). LCMS(Analytical Method D) Rt = 3.81 min, MS (ESIpos): m/z = 425 (M + H)⁺. 77

N-[(1R)-1-(6- Methylpyridazin- 3-yl)ethyl]-3- (5-methyl- 1,3-thiazol-2-yl)-5-[(3R)- tetrahydrofuran- 3-ylmethoxy] benzomide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.02 7.96 (m, 2H), 7.67 7.58 (m, 2H), 7.55-7.45 (m,3H), 5.50 (p, J = 7.0 Hz, 1H), 4.10-3.86 (m, 4H), 3.80 (q, J = 7.8 Hz,1H), 3.71 (dd, J = 8.9, 5.4 Hz, 1H), 2.81-2.72 (m, 4H), 2.53 (s, 3H),2.13 (dtd, J = 13.6, 8.1, 5.6 Hz, 1H), 1.81-1.68 (m, 4H). LCMS(Analytical Method D) Rt = 3.70 min, MS (ESIpos): m/z = 439 (M + H)⁺. 78

N-[1-(5- Chloro-3- fluoropyridin- 2-yl)ethyl]-3- (5-methyl-1,3-thiazol-2- yl)-5-[(3R)- tetrahydrofuran- 3-ylmethoxy] benzamide ¹HNMR (500 MHz, CDCl₃): δ [ppm] = 8.39 (d, J = 1.8 Hz, 1H), 7.90 (s, 1H),7.61-7.52 (m, 3H), 7.50-7.41 (m, 2H), 5.66 (p, J = 6.9 Hz, 1H), 4.10-3.87 (m, 4H), 3.80 (q, J = 7.8 Hz, 1H), 3.72 (dd, J = 8.8, 5.3 Hz, 1H),2.77 (hept, J = 6.2 Hz, 1H), 2.54 (s, 3H), 2.13 (dtd, J = 13.4, 8.1, 5.6Hz, 1H), 1.76 (dq, J = 12.8, 7.0 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H). LCMS(Analytical Method D) Rt = 4.55 min, MS (ESIpos): m/z = 476 (M + H)⁺. 79

3-(5-Methyl- 1,3-thiazol-2- yl)-5-[(3R)- tetrahydrofuran- 3-ylmethoxy]-N-[(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl] benzamide ¹H NMR(500 MHz, CDCl₃): δ [ppm] = 7.88-7.79 (m, 2H), 7.74 (d, J = 8.7 Hz, 1H),7.59-7.49 (m, 3H), 7.41- 7.36 (m, 1H), 5.60 (p, J = 7.0 Hz, 1H),4.07-3.86 (m, 4H), 3.79 (q, J = 7.8 Hz, 1H), 3.70 (dd, J = 8.9, 5.3 Hz,1H), 2.75 (hept, J = 6.5 Hz, 1H), 2.52 (d, J = 0.9 Hz, 3H), 2.12 (dtd, J= 13.4, 8.1, 5.6 Hz, 1H), 1.77-1.69 (m, 4H). LCMS (Analytical Method F)Rt = 3.46 min, MS (ESIpos): m/z = 493.1 (M + H)⁺. 80

N-[1-(3- Chloro-5- fluoropyridin- 2-yl)ethyl]-3- (5-methyl-1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- yloxy) benzamide ¹H NMR(500 MHz, CDCl₃): δ [ppm] = 8.39 (d, J = 2.5 Hz, 1H), 7.90-7.85 (m, 1H),7.67-7.61 (m, 1H), 7.60- 7.56 (m, 1H), 7.55-7.49 (m, 2H), 7.47-7.43 (m,1H), 5.81-5.71 (m, 1H), 4.70-4.61 (m, 1H), 4.04-3.95 (m, 2H), 3.64-3.55(m, 2H), 2.53 (d, J = 1.1 Hz, 3H), 2.11-2.01 (m, 2H), 1.88 1.76 (m, 2H),1.54 (d, J = 6.7 Hz, 3H). LCMS (Analytical Method F) Rt = 3.77 min, MS(ESIpos): m/z = 476.1 (M + H)⁺. 81

N-[1-(5- Chloro-3- fluoropyridin- 2-yl)ethyl]-3- (5-methyl-1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- yloxy) benzamide ¹H NMR(500 MHz, CDCl₃): δ [ppm] = 8.38 (d, J = 1.8 Hz, 1H), 7.89-7.85 (m, 1H),7.61-7.58 (m, 1H), 7.57- 7.51 (m, 2H), 7.50-7.46 (m, 1H), 7.45-7.42 (m,1H), 5.71-5.61 (m, 1H), 4.70-4.61 (m, 1H), 4.04-3.95 (m, 2H), 3.64-3.55(m, 2H), 2.53 (d, J = 1.1 Hz, 3H), 2.11-2.01 (m, 2H), 1.88-1.76 (m, 2H),1.56 (d, J = 6.8 Hz, 3H). LCMS (Analytical Method F) Rt = 3.78 min, MS(ESIpos): m/z = 476.1 (M + H)⁺. 82

N-[(6- Methylpyridazin- 3-yl)methyl]-3- (5-methyl- 1,3-thiazol-2- yl)-5-(tetrahydro- 2H-pyran-4- yloxy) benzamide ¹H NMR (500 MHz, CDCl₃): δ[ppm] = 7.89-7.85 (m, 1H), 7.67-7.62 (m, 1H), 7.62-7.59 (m, 1H),7.52-7.48 (m, 1H), 7.48-7.43 (m, 2H), 7.34 (d, J = 8.6 Hz, 1H), 4.91 (d,J = 5.2 Hz, 2H), 4.69-4.61 (m, 1H), 4.03-3.94 (m, 2H), 3.64-3.56 (m,2H), 2.72 (s, 3H), 2.52 (d, J = 1.1 Hz, 3H), 2.10- 2.01 (m, 2H),1.87-1.76 (m, 2H). LCMS (Analytical Method F) Rt = 2.48 min, MS(ESIpos): m/z = 425.2 (M + H)⁺. 83

N-[(5- Methylpyrazin- 2-yl)methyl]-3- (5-methyl- 1,3-thiazol-2- yl)-5-(tetrahydro- 2H-pyran-4- yloxy) benzamide ¹H NMR (500 MHz, CDCl₃): δ[ppm] = 8.58-8.54 (m, 1H), 8.44-8.40 (m, 1H), 7.88-7.84 (m, 1H),7.61-7.56 (m, 1H), 7.53-7.49 (m, 1H), 7.49- 7.43 (m, 1H), 7.26-7.23 (m,1H), 4.77 (d, J = 5.2 Hz, 2H), 4.69-4.60 (m, 1H), 4.03-3.94 (m, 2H),3.64- 3.55 (m, 2H), 2.57 (s, 3H), 2.52 (d, J = 1.1 Hz, 3H), 2.10-2.01(m, 2H), 1.87- 1.76 (m, 2H). LCMS (Analytical Method F) Rt = 2727 min,MS (ESIpos): m/z = 425.1 (M + H)⁺. 84

N-[(1R)-1-(5- Methylpyrazin- 2-yl)ethyl]- 3-(5-methyl- 1,3-thiazol-2-yl)-5- (tetrahydro- 2H-pyran-4- yloxy) benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.56-8.51 (m, 1H), 8.44-8.39 (m, 1H), 7.87-7.83 (m,1H), 7.60-7.55 (m, 1H), 7.53-7.51 (m, 1H), 7.45- 7.41 (m, 1H), 7.32-7.27(m, 1H), 5.48-5.38 (m, 1H), 4.69-4.60 (m, 1H), 4.03-3.94 (m, 2H),3.64-3.55 (m, 2H), 2.57 (s, 3H), 2.53 (d, J = 1.1 Hz, 3H), 2.11 2.02 (m,2H), 1.87 1.75 (m, 2H), 1.60 (d, J = 6.8 Hz, 3H). LCMS (AnalyticalMethod F) Rt = 2.97 min, MS (ESIpos): m/z = 439.2 (M + H)⁺. 85

3-(5-Methyl- 1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- yloxy)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide ¹H NMR(500 MHz, CDCl₃): δ [ppm] = 8.93 (s, 2H), 7.86-7.81 (m, 1H), 7.56- 7.50(m, 2H), 7.43-7.38 (m, 1H), 6.65 (d, J = 6.5 Hz, 1H), 5.40-5.31 (m, 1H),4.68-4.59 (m, 1H), 4.02- 3.94 (m, 2H), 3.64-3.55 (m, 2H), 2.54 (d, J =1.1 Hz, 3H), 2.09-2.02 (m, 2H), 1.86-1.75 (m, 2H), 1.72 (d, J = 7.2 Hz,3H). LCMS (Analytical Method F) Rt = 3.52 min, MS (ESIpos): m/z = 493.1(M + H)⁺. 86

N-[(1R)-1-(6- Methoxypyridin- 3-yl)ethyl]-3- (5-methyl- 1,3-thiazol-2-yl)-5- (tetrahydro- 2H-pyran-4- yloxy) benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.22 (d, J = 2.5 Hz, 1H), 7.78 (s, 1H), 7.61 (dd, J =8.6, 2.5 Hz, 1H), 7.54- 7.52 (m, 1H), 7.51 (d, J = 1.2 Hz, 1H),7.44-7.41 (m, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H),5.35- 5.26 (m, 1H), 4.64 (dt, J = 7.8, 3.8 Hz, 1H), 4.03-3.95 (m, 2H),3.93 (s, 3H), 3.60 (t, J = 8.6 Hz, 2H), 2.53 (d, J = 1.1 Hz, 3H), 2.04(s, 2H), 1.89- 1.75 (m, 2H), 1.62 (d, J = 7.0 Hz, 3H). LCMS (AnalyticalMethod F) Rt = 3.27 min, MS (ESIpos): m/z = 454.1 (M + H)⁺. 87

N-[(1R)-1-(6- Methylpyridazin- 3-yl)ethyl]-3- (5-methyl- 1,3-thiazol-2-yl)-5- (tetrahydro- 2H-pyran-4- yloxy) benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 7.87 (t, J = 1.4 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H),7.62-7.58 (m, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.45-7.43 (m, 1H), 7.40 (d,J = 8.5 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 5.45 (q, J = 6.9 Hz, 1H),4.65 (dt, J = 8.0, 4.0 Hz, 1H), 4.05-3.94 (m, 2H), 3.61 (ddt, J = 8.8,5.5, 2.8 Hz, 2H), 2.73 (s, 3H), 2.53 (d, J = 1.1 Hz, 3H), 2.07 (d, J =28.7 Hz, 2H), 1.82 (ddt, J = 12.6, 8.0, 4.1 Hz, 2H), 1.68 (d, J = 6.8Hz, 3H). LCMS (Analytical Method F) Rt = 2.61 min, MS (ESIpos): m/z =439.2 (M + H)⁺. 88

N-[(6- Methoxy- pyridazin-3- yl)methyl]-3- (5-methyl- 1,3-thiazol-2-yl)-5- (tetrahydro- 2H-pyran-4- yloxy) benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 7.87 (t, J = 1.4 Hz, 1H), 7.63-7.60 (m, 1H), 7.51 (d,J = 1.2 Hz, 1H), 7.50- 7.41 (m, 3H), 7.01 (d, J = 9.1 Hz, 1H), 4.86 (d,J = 5.1 Hz, 2H), 4.66 (dq, J = 7.6, 3.8 Hz, 1H), 4.14 (s, 3H), 4.05-3.96(m, 2H), 3.61 (ddd, J = 11.6, 8.2, 3.2 Hz, 2H), 2.53 (d, J = 1.1 Hz,3H), 2.12-2.02 (m, 2H), 1.82 (dtd, J = 12.0, 8.1, 3.8 Hz, 2H). LCMS(Analytical Method F) Rt = 2.82 min, MS (ESIpos): m/z = 441.1 (M + H)⁺.89

3-(5-Methyl- 1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- yloxy)-N-{(1R)-1-[6- (trifluoromethyl) pyridazin- 3-yl]ethyl} benzamide ¹H NMR(500 MHz, CDCl₃): δ [ppm] = 7.92 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.75(d, J = 8.7 Hz, 1H), 7.59 (dd, J = 2.3, 1.5 Hz, 1H), 7.54 (t, J = 2.4Hz, 2H), 7.46-7.41 (m, 1H), 5.60 (p, J = 7.0 Hz, 1H), 4.64 (tt, J = 7.8,3.8 Hz, 1H), 3.98 (dq, J = 9.9, 5.4, 4.9 Hz, 2H), 3.60 (ddt, J = 11.6,6.2, 2.6 Hz, 2H), 2.54 (d, J = 1.1 Hz, 3H), 2.09- 2.01 (m, 2H), 1.79(dd, J = 28.1, 5.6 Hz, 5H). LCMS (Analytical Method F) Rt = 3.44 min, MS(ESIpos): m/z = 492.0 (M + H)⁺.

In analogy to the procedure described for Example 7 the followingexamples were prepared using the appropriate carboxylic acid and amineas starting materials.

Ex. Structure Name Analytical Data 90

3-(5-Methyl- 1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4-yloxy)-N-{(1R)- 1-[2- (trifluorometh- yl)pyrimidin-5- yl]propyl}benz-amide ¹H NMR (500 MHz, CDCl₃): δ [ppm] = 8.91 (s, 2H), 7.83 (s, 1H),7.57- 7.53 (m, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H),6.61 (d, J = 6.9 Hz, 1H), 5.10 (q, J = 7.2 Hz, 1H), 4.63 (tt, J = 8.0,3.8 Hz, 1H), 4.03-3.95 (m, 2H), 3.63- 3.56 (m, 2H), 2.54 (d, J = 0.9 Hz,3H), 2.10-1.97 (m, 4H), 1.81 (s, 2H), 1.08 (t, J = 7.4 Hz, 3H). LCMS(Analytical Method F) Rt - 3.74 min, MS (ESIpos): m/z = 507.3 (M + H)⁺.91

N-[(1R)-1-(6- Methylpyridin- 3-yl)ethyl]-3- (5-methyl-1,3-thiazol-2-yl)-5- (tetrahydro- 2H-pyran-4- yloxy)benzamide ¹H NMR (500MHz, CDCl₃): δ [ppm] = 8.56 (d, J = 2.3 Hz, 1H), 7.79 (t, J = 1.4 Hz,1H), 7.60 (dd, J = 8.0, 2.4 Hz, 1H), 7.53 (dd, J = 2.4, 1.5 Hz, 1H),7.51 (d, J = 1.2 Hz, 1H), 7.44-7.40 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H),6.43 (d, J = 7.4 Hz, 1H), 5.32 (p, J = 7.0 Hz, 1H), 4.64 (tt, J = 7.9,3.8 Hz, 1H), 3.98 (dt, J = 10.4, 4.5 Hz, 2H), 3.64-3.55 (m, 2H), 2.55(s, 3H), 2.53 (d, J = 1.1 Hz, 3H), 2.09-2.02 (m, 2H), 1.81 (ddq, J =12.8, 8.4, 4.0 Hz, 2H), 1.63 (d, J = 7.0 Hz, 3H). LCMS (AnalyticalMethod D) Rt = 3.18 min, MS (ESIpos): m/z = 438.1 (M + H)⁺. 92

N-[(1R)-1-(5- Methyl-1,3,4- thiadiazol-2- yl)ethyl]-3-(5- methyl-1,3-thiazol-2-yl)-5- (tetrahydro- 2H-pyran-4- yloxy)benzamide ¹H NMR (500MHz, CDCl₃): δ [ppm] = 7.83 (t, J = 1.4 Hz, 1H), 7.59 (dd, J = 2.4, 1.5Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.45-7.42 (m, 1H), 7.01 (d, J = 7.6Hz, 1H), 5.69 (p, J = 6.9 Hz, 1H), 4.65 (dt, J = 8.0, 4.1 Hz, 1H),4.03-3.95 (m, 2H), 3.61 (ddd, J = 11.7, 8.4, 3.2 Hz, 2H), 2.77 (s, 3H),2.53 (d, J = 1.1 Hz, 3H), 2.10-2.02 (m, 2H), 1.86- 1.81 (m, 2H), 1.80(d, J = 6.9 Hz, 3H). LCMS (Analytical Method F) 99% @ Rt = 2.87 min, MS(ESIpos): m/z = 445.2 (M + H)⁺.

In analogy to the procedure described for Example 1 the followingexamples were prepared using the appropriate carboxylic acid and amineas starting materials.

Ex. Structure Name Analytical Data 93

N-[(6- Methyl- pyridazin-3- yl)methyl]-3- (5-methyl- 1,3-thiazol-2-yl)-5- (tetrahydro- 2H-pyran-4- ylmethoxy) benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 7.95-7.91 (m, 1H), 7.90 (s, 1H), 7.61- 7.56 (m, 2H),7.50 (d, J = 1.1 Hz, 1H), 7.45 (dd, J = 2.3, 1.4 Hz, 1H), 7.43-7.39 (m,1H), 4.93 (d, J = 5.1 Hz, 2H), 4.05-3.99 (m, 2H), 3.92 (d, J = 6.5 Hz,2H), 3.45 (td, J = 11.9, 2.0 Hz, 2H), 2.74 (s, 3H), 2.51 (d, J = 1.0 Hz,3H), 2.15-2.03 (m, 1H), 1.81-1.73 (m, 2H), 1.46 (ddd, J = 12.1, 4.5 Hz,2H). LCMS (Analytical Method F) Rt = 2.69 min, MS (ESIpos): m/z = 439.2(M + H)⁺. 94

N-[(1R)-1-(5- Methylpyrazin- 2-yl)ethyl]- 3-(5-methyl- 1,3-thiazol-2-yl)-5- (tetrahydro- 2H-pyran-4- ylmethoxy) benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.54 (d, J = 1.4 Hz, 1H), 8.42 (s, 1H), 7.89 (s, 1H),7.56 (dd, J = 2.4, 1.5 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.41 (dd, J =2.3, 1.5 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 5.43 (p, J = 6.9 Hz, 1H),4.02 (dd, J = 11.4, 3.0 Hz, 2H), 3.92 (d, J = 6.4 Hz, 2H), 3.45 (td, J =11.8, 2.0 Hz, 2H), 2.57 (s, 3H), 2.53 (d, J = 1.1 Hz, 3H), 2.15-2.04 (m,1H), 1.77 (d, J = 12.5 Hz, 2H), 1.61 (d, J = 6.9 Hz, 3H), 1.48 (qd, J =12.1, 4.5 Hz, 2H). LCMS (Analytical Method F) Rt = 3.18 min, MS(ESIpos): m/z = 453.2 (M + H)⁺. 95

N-[1-(5- Chloro-3- fluoropyridin- 2-yl)ethyl]-3- (5-methyl-1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran--4- ylmethoxy) benzamide ¹HNMR (500 MHz, CDCl₃): δ [ppm] = 8.38 (d, J = 1.8 Hz, 1H), 7.92 (s, 1H),7.62-7.56 (m, 2H), 7.55 (d, J = 1.2 Hz, 1H), 7.47 (dd, J = 8.9, 2.0 Hz,1H), 7.43 (dd, J = 2.3, 1.5 Hz, 1H), 5.66 (p, J = 6.7 Hz, 1H), 4.03 (dd,J = 11.4, 3.1 Hz, 2H), 3.94 (d, J = 6.4 Hz, 2H), 3.45 (td, J= 11.8, 2.0Hz, 2H), 2.54 (d, J = 1.1 Hz, 3H), 2.15-2.05 (m, 1H), 1.82-1.74 (m, 2H),1.56 (d, J = 6.8 Hz, 3H), 1.48 (qd, J = 12.2, 4.7 Hz, 2H). LCMS(Analytical Method D) Rt = 4.73 min, MS (ESIpos): m/z = 507 (M + H)⁺. 96

N-[1-(3- Chloro-5- fluoropyridin- 2-yl)ethyl]-3- (5-methyl-1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- ylmethoxy) benzamide ¹HNMR (500 MHz, CDCl₃): δ [ppm] = 8.39 (d, J = 2.5 Hz, 1H), 7.88 (t, J =1.3 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.61-7.48 (m, 3H), 7.42 (dd, J =2.4, 1.5 Hz, 1H), 5.75 (p, J = 6.7 Hz, 1H), 4.02 (dd, J = 11.4, 3.1 Hz,2H), 3.93 (d, J = 6.4 Hz, 2H), 3.45 (td, J = 11.8, 2.0 Hz, 2H), 2.53 (d,J = 1.1 Hz, 3H), 2.09 (tdd, J = 15.6, 6.8, 3.6 Hz, 1H), 1.80-1.74 (m,2H), 1.53 (d, J = 6.7 Hz, 5H), 1.52-1.43 (m, 2H). LCMS (AnalyticalMethod F) Rt = 3.97 min, MS (ESIpos): m/z = 490.1 (M + H)⁺. 97

N-[(5- Methylpyrazin- 2- yl)methyl]-3- (5-methyl- 1,3-thiazol-2- yl)-5-(tetrahydro- 2H-pyran-4- ylmethoxy) benzamide ¹H NMR (500 MHz, CDCl₃): δ[ppm] = 8.56 (d, J = 1.2 Hz, 1H), 8.42 (s, 1H), 7.87 (s, 1H), 7.57 (dd,J = 2.4, 1.5 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.43 (dd, J = 2.4, 1.5Hz, 1H), 7.26-7.22 (m, 1H), 4.77 (d, J = 5.2 Hz, 2H), 4.06- 4.00 (m,2H), 3.93 (d, J = 6.5 Hz, 2H), 3.45 (td, J= 11.9, 2.0 Hz, 2H), 2.58 (s,3H), 2.53 (d, J = 1.1 Hz, 3H), 2.15-2.04 (m, 1H), 1.81-1.74 (m, 2H),1.48 (ddd, J = 12.1, 4.5 Hz, 2H). LCMS (Analytical Method F) Rt = 2.96min, MS (ESIpos): m/z = 439.2 (M + H)⁺. 98

3-(5-Methyl- 1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- ylmethoxy)-N-[(1R)-1-[2- (trifluorometh- yl)pyrimidin- 5- yl]ethyl] benzamide ¹HNMR (500 MHz, CDCl₃): δ [ppm] = 8.93 (s, 2H), 7.86 (t, J = 1.3 Hz, 1H),7.52 (d, J = 1.2 Hz, 1H), 7.50 (dd, J = 2.4, 1.5 Hz, 1H), 7.38 (dd, J =2.3, 1.6 Hz, 1H), 6.76 (d, J = 6.6 Hz, 1H), 5.36 (p, J = 7.1 Hz, 1H),4.02 (dd, J = 11.3, 3.1 Hz, 2H), 3.90 (d, J= 6.4 Hz, 2H), 3.45 (td, J =11.8, 2.0 Hz, 2H), 2.53 (d, J = 1.1 Hz, 3H), 2.14-2.03 (m, 1H),1.79-1.73 (m, 2H), 1.71 (d, J = 7.2 Hz, 3H), 1.47 (qd, J = 12.1, 4.6 Hz,2H). LCMS (Analytical Method F): Rt = 3.72 min, MS (ESIpos): m/z = 507.1(M + H)⁺. 99

N-[(1R)-1-(6- Methyl- pyridazin-3- yl)ethyl]-3- (5-methyl-1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- ylmethoxy) benzamide ¹HNMR (500 MHz, CDCl₃): δ [ppm] = 8.01-7.94 (m, 2H), 7.65-7.57 (m, 2H),7.53 (s, 1H), 7.51-7.44 (m, 2H), 5.50 (p, J = 7.0 Hz, 1H), 4.02 (dd, J =11.3, 3.4 Hz, 2H), 3.93 (d, J = 6.4 Hz, 2H), 3.45 (td, J = 11.8, 1.7 Hz,2H), 2.78 (s, 3H), 2.53 (s, 3H), 2.13-2.04 (m, 1H), 1.81-1.67 (m, 5H),1.47 (qd, J = 12.1, 4.4 Hz, 2H). LCMS (Analytical Method D) Rt = 3.84min, MS (ESIpos): m/z = 453 (M + H)⁺. 100

N-[(1R)-1-(6- Methyl- pyridazin-3- yl)ethyl]-3- [(2- methylpyridin-4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2- yl)benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.38 (d, J = 5.5 Hz, 1H), 8.18 (t, J = 1.4 Hz, 1H),7.90 (d, J = 7.2 Hz, 1H), 7.79-7.75 (m, 1H), 7.61-7.57 (m, 1H), 7.53 (d,J = 1.1 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H),6.75-6.68 (m, 2H), 5.45 (p, J = 6.8 Hz, 1H), 2.73 (s, 3H), 2.53 (d, J =0.9 Hz, 3H), 2.51 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H). LCMS (AnalyticalMethod D) Rt = 2.87 min, MS (ESIpos): m/z = 446 (M + H)⁺. 101

N-[(6- Methyl- pyridazin-3- yl)methyl]-3- [(2- methylpyridin-4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2- yl)benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.38 (d, J = 5.6 Hz, 1H), 8.18 (t, J = 1.5 Hz, 1H),7.79-7.76 (m, 1H), 7.73 (t, J = 4.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.52 (d,J = 1.1 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H),6.75-6.69 (m, 2H), 4.91 (d, J= 5.1 Hz, 2H), 2.72 (s, 3H), 2.53 (d, J =1.0 Hz, 3H), 2.52 (s, 3H). LCMS (Analytical Method D) Rt = 2.80 min, MS(ESIpos): m/z = 432.1 (M + H)⁺. 102

N-[(1R)-1-(5- Methylpyrazin- 2-yl)ethyl]- 3-[(2- methylpyridin-4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2- yl)benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.56 (d, J = 1.4 Hz, 1H), 8.43 (s, 1H), 8.41 (d, J =5.6 Hz, 1H), 8.18 (t, J = 1.5 Hz, 1H), 7.80-7.75 (m, 1H), 7.63- 7.58 (m,1H), 7.56 (d, J = 1.2 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 6.79- 6.72 (m,2H), 5.45 (p, J = 6.9 Hz, 1H), 2.60 (s, 3H), 2.56 (d, J = 1.1 Hz, 3H),2.54 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). LCMS (Analytical Method D) Rt =3.00 min, MS (ESIpos): m/z = 446.1 (M + H)⁺. 103

3-[(2- Methylpyridin- 4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2-yl)-N-{(1R)-1- [2- (trifluorometh- yl)pyrimidin- 5- yl]ethyl} benzamide¹H NMR (500 MHz, CDCl₃): δ [ppm] = 8.94 (s, 2H), 8.39 (d, J = 5.7 Hz,1H), 8.13 (t, J = 1.5 Hz, 1H), 7.74-7.70 (m, 1H), 7.58-7.53 (m, 2H),6.73 (d, J = 2.3 Hz, 1H), 6.71 (dd, J = 5.6, 2.3 Hz, 1H), 6.65 (d, J =6.5 Hz, 1H), 5.37 (p, J = 7.0 Hz, 1H), 2.54 (d, J = 1.0 Hz, 3H), 2.52(s, 3H), 1.73 (d, J= 7.1 Hz, 3H). LCMS (Analytical Method D) Rt = 3.28min, MS (ESIpos): m/z = 500.1 (M + H)⁺. 104

N-[(5- Methylpyrazin- 2- yl)methyl]-3- [(2- methylpyridin- 4-yl)oxy]-5-(5-methyl- 1,3-thiazol-2- yl)benzamide ¹H NMR (500 MHz, CDCl₃): δ [ppm]= 8.56 (d, J = 1.1 Hz, 1H), 8.42 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.17(t, J = 1.5 Hz, 1H), 7.78-7.73 (m, 1H), 7.61- 7.57 (m, 1H), 7.53 (d, J =1.1 Hz, 1H), 7.27 (s, 1H), 6.73 (dt, J = 8.1, 2.3 Hz, 2H), 4.78 (d, J =5.1 Hz, 2H), 2.58 (s, 3H), 2.54 (d, J = 1.1 Hz, 3H), 2.52 (s, 3H). LCMS(Analytical Method D) Rt = 2.90 min, MS (ESIpos): m/z = 432.1 (M + H)⁺.105

3-[(2- Methylpyridin- 4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2-yl)-N-{(1R)-1- [6- (trifluorometh- yl)pyridazin- 3- yl]ethyl} benzamide¹H NMR (500 MHz, CDCl₃): δ [ppm] = 8.38 (dd, J = 5.3, 0.9 Hz, 1H), 8.17(t, J = 1.5 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.78-7.72 (m, 2H), 7.69(d, J = 7.3 Hz, 1H), 7.61-7.56 (m, 1H), 7.53 (d, J = 1.2 Hz, 1H),6.77-6.71 (m, 2H), 5.60 (p, J = 7.0 Hz, 1H), 2.56- 2.51 (m, 6H), 1.93(d, J= 7.1 Hz, 0H), 1.76 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method F)Rt = 2.16 min, MS (ESIpos): m/z = 499.0 (M + H)⁺.

Example 1063-[(2-methylpyridin-4-yl)oxy]-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

3-Bromo-5-[(2-methylpyridin-4-yl)oxy]benzoic acid

Intermediate 1 (2.3 g, 9.95 mmol), 4-bromo-2-methylpyridine (2.05 g,11.95 mmol) and Cs₂CO₃ (19.5 g, 59.7 mmol) in DMF (150 mL) were stirredat 120° C. for 48 hours. The reaction mixture was cooled to RT,filtrated and evaporated to dryness. The crude material was purified bycolumn chromatography (silica gel, hexane/EE gradient) to afford thetitle compound 1.1 g (36% yield).

3-Bromo-5-[(2-methylpyridin-4-yl)oxy]-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]benzamide

3-Bromo-5-[(2-methylpyridin-4-yl)oxy]benzoic acid (273 mg, 0.89 mmol),(1R)-1-(2-methylpyrimidin-5-yl)ethanamine dihydrochloride (205 mg, 0.97mmol), DIPEA (0.76 ml, 4.4 mmol) and HATU (371 mg, 0.97 mmol) weredissolved in DMF. The reaction mixture was stirred overnight at RT.Additional (1R)-1-(2-methylpyrimidin-5-yl)ethanamine dihydrochloride(205 mg, 0.97 mmol), DIPEA (0.76 ml, 4.4 mmol) and HATU (371 mg, 0.97mmol) was added and the reaction mixture was stirred at 60° C. untilcomplete conversion and evaporated to dryness. The crude material waspurified by column chromatography (silica gel, hexane/EE gradient) toafford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.52 (d, J=7.07 Hz, 3 H) 2.43 (s, 3 H)2.58 (s, 3 H) 5.13 (s, 1 H) 6.78-6.82 (m, 1 H) 6.87 (d, J=2.53 Hz, 1 H)7.63 (t, J=1.39 Hz, 2 H) 7.99 (t, J=1.64 Hz, 1 H) 8.36 (d, J=5.56 Hz, 1H) 8.69 (s, 2 H) 9.03 (d, J=7.33 Hz, 1 H).

(3-[(2-Methylpyridin-4-yl)oxy]-5-{[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]carbamoyl}phenyl)boronicacid

3-Bromo-5-[(2-methylpyridin-4-yl)oxy]-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]benzamide(0.97 g, 77% purity, 1.75 mmol), bis(pinacolato)diborane (1.11 g, 4.37mmol) and potassium acetate (0.58 g, 5.94 mmol) were dissolved in1,4-dioxane. Pd(dppf)Cl₂.CH₂Cl₂ (80 mg, 0.1 mmol) was added and thereaction mixture was stirred at 100° C. for 12 hours. The reactionmixture was concentrated in vacuo and purified by column chromatography(silica gel, hexane/EE gradient) to afford the title compound 96 mg (14%yield).

3-[(2-Methylpyridin-4-yl)oxy]-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

(3-[(2-methylpyridin-4-yl)oxy]-5-{[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]carbamoyl}phenyl)boronicacid (96 mg, 0.24 mmol) and 2-bromo-5-methyl-1,3-thiazole (65 mg, 0.37mmol) were dissolved in 1M K₂CO₃ aqueous solution (0.59 mL) and THF (4mL). Pd(dppf)Cl₂.CH₂Cl₂ (30 mg, 0.04 mmol) was added and the reactionmixture heated to reflux for 2 hours. The reaction mixture wasconcentrated under reduced pressure. Crude material was purified bypreparative HPLC (method 2, rt: 1.03 min) to afford the title compound27 mg (25% yield).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.54 (d, J=7.16 Hz, 3 H) 2.43 (s, 3 H)2.59 (s, 3 H) 5.17 (s, 1 H) 6.84 (dd, J=5.65, 2.45 Hz, 1 H) 6.91 (d,J=2.26 Hz, 1 H) 7.66 (d, J=1.13 Hz, 1 H) 7.71-7.78 (m, 2 H) 8.24 (s, 1H) 8.37 (d, J=5.65 Hz, 1 H) 8.72 (s, 2 H) 9.14 (d, J=7.35 Hz, 1 H).

In analogy to the procedure described for Example 1 the followingexample was prepared using the appropriate carboxylic acid and amine asstarting materials.

Ex. Structure Name Analytical Data 107

N-[(1R)-1-(6- Methylpyridin- 3-yl)ethyl]- 3-[(2- methylpyridin-4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2- yl)benzamide ¹H NMR (400 MHz,CDCl₃): δ [ppm] = 8.50 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 5.7 Hz, 1H),8.11 (t, J = 1.5 Hz, 1H), 7.78 (t, J = 1.4 Hz, 0H), 7.70-7.65 (m, 1H),7.60-7.53 (m, 2H), 7.49 (d, J = 1.2 Hz, 1H), 7.39-7.37 (m, 0H), 7.10 (d,J = 8.0 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.69-6.62 (m, 2H), 5.30 (dd,J = 14.5, 7.4 Hz, 1H), 2.50 (d, J = 1.2 Hz, 6H), 2.45 (s, 3H), 1.60 (d,J = 7.0 Hz, 3H). LCMS (Analytical Method F) Rt = 1.25 min, MS (ESIpos):m/z = 44.52 (M + H)⁺.

Example 1083-[(6-Methylpyridin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5N (375 mg, 1.15 mmol), Intermediate VI (242 mg, 1.26mmol), DIPEA (0.8 ml, 4.6 mmol) and HATU (612 mg, 1.61 mmol) weredissolved in DMF (13.3 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The crude material wasextracted three times with EE and evaporated to dryness again. Theremaining crude material was purified by preparative HPLC (method 1, rt:1.16 min) to afford the title compound 18.5 mg (3.2% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, J=7.10 Hz, 3 H) 5.24-5.33 (m,1 H) 7.35 (d, J=8.36 Hz, 1 H) 7.51 (dd, J=8.49, 2.91 Hz, 1 H) 7.60 (t,J=1.39 Hz, 2 H) 7.64 (d, J=1.27 Hz, 1 H) 8.12 (t, J=1.52 Hz, 1 H) 8.36(d, J=2.53 Hz, 1 H) 9.11 (s, 2 H) 9.23-9.29 (m, 1 H).

In analogy to the procedure described for Example 7 the followingexamples were prepared using the appropriate carboxylic acid and amineas starting materials.

Ex. Structure Name Analytical Data 109

N-[(1R)-1-(5- Methylpyrazin- 2-yl)ethyl]-3- [(5-methyl- 1,3,4-thiadiazol-2- yl)oxy]-5-(5- methyl-1,3- thiazol-2- yl)benzamide ¹H NMR(500 MHz, CDCl): δ [ppm] = 8.53 (d, J = 1.2 Hz, 1H), 8.42 (s, 1H), 8.18(s, 1H), 8.00-7.97 (m, 1H), 7.81-7.77 (m, 1H), 7.54 (d, J = 1.1 Hz, 1H),7.36 (d, J = 7.5 Hz, 1H), 5.43 (p, J = 6.8 Hz, 1H), 2.69 (s, 3H), 2.58(s, 3H), 2.54 (d, J = 0.9 Hz, 3H), 1.60 (d, J = (d, J = 6.8 Hz, 3H).LCMS (Analytical Method F) Rt = 2.82 min, MS (ESIpos): m/z = 453.2 (M +H)⁺. 110

N-[(1R)-1-(6- Methylpyridazin- 3-yl)ethyl]- 3-[(5-methyl- 1,3,4-thiadiazol-2- yl)oxy]-5-(5- methyl-1,3- thiazol-2- yl)benzamide ¹H NMR(500 MHz, CDCl₃): δ [ppm] = 8.21 (t, J = 1.4 Hz, 1H), 8.02- 8.00 (m,1H), 7.86 (d, J = 7.2 Hz, 1H), 7.82-7.79 (m, 1H), 7.53 (d, J = 1.1 Hz,1H), 7.40 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 5.46 (p, J =6.9 Hz, 1H), 2.73 (s, 3H), 2.68 (s, 3H), 2.53 (d, J = 1.0 Hz, 3H), 1.68(d, J = 6.8 Hz, 3H). LCMS (Analytical Method F) Rt = 2.48 min, MS(ESIpos): m/z = 453.2 (M + H)⁺. 111

3-[(5-Methyl- 1,3,4- thiadiazol-2- yl)oxy]-5-(5- methyl-1,3-thiazol-2-yl)- N-[(1R)-1-[2- (trifluorometh- yl)pyrimidin-5- yl]ethyl]benzamide ¹H NMR (500 MHz, CDCl₃): δ [ppm] = 8.95 (s, 2H), 8.13 (s, 1H),7.97- 7.92 (m, 1H), 7.81-7.76 (m, 1H), 7.53 (d, J = 1.1 Hz, 1H), 6.97(d, J = 6.6 Hz, 1H), 5.37 (p, J = 7.0 Hz, 1H), 2.69 (s, 3H), 2.54 (d, J= 0.9 Hz, 3H), 1.72 (d, J = 7.2 Hz, 3H). LCMS (Analytical Method F) Rt =3.41 min, MS (ESIpos): m/z = 507.1 (M + H)⁺. 112

N-[(1R)-1-(5- Methylpyrazin- 2-yl)ethyl]-3- (5-methyl-1,3-thiazol-2-yl)-5- (1,3-thiazol-2- yloxy)benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.53 (d, J = 1.4 Hz, 1H), 8.41 (s, 1H), 8.17 t, J =1.5 Hz, 1H), 7.97 (dd, J = 2.3, 1.6 Hz, 1H), 7.78 (dd, J = 2.3, 1.6 Hz,1H), 7.54 (d, J = 1.2 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.25 (d, J =3.8 Hz, 1H), 6.88 (d, J = 3.8 Hz, 1H), 5.43 (p, J = 6.8 Hz, 1H), 2.58(s, 3H), 2.54 (d, J = 1.1 Hz, 3H), 1.60 (d, J = 6.8 Hz, 3H). LCMS(Analytical Method D) Rt = 4.04 min, MS (ESIpos): m/z = 438.1 (M + H)⁺.113

N-[(1R)-1-(6- Methylpyridazin- 3-yl)ethyl]- 3-(5-methyl- 1,3-thiazol-2-yl)-5-(1,3- thiazol-2- yloxy)benzamide ¹H NMR (500 MHz, CDCl₃): δ [ppm]= 8.19 (t, J = 1.5 Hz, 1H), 8.00 (dd, J = 2.3, 1.5 Hz, 1H), 7.83 (d, J =7.2 Hz, 1H), 7.80 (dd, J = 2.2, 1.6 Hz, 1H), 7.53 (d, J = 1.1 Hz, 1H),7.39 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 3.8 Hz,1H), 6.87 (d, J = 3.8 Hz, 1H), 5.50- 5.43 (m, 1H), 2.73 (s, 3H), 2.53(d, J = 1.1 Hz, 3H), 1.68 (d, J = 6.8 Hz, 3H). LCMS (Analytical MethodD) Rt = 3.77 min, MS (ESIpos): m/z = 438.0 (M + H)⁺. 114

N-[(1R)-1-(6- Methylpyridin- 3-yl)ethyl]-3- (5-methyl-1,3-thiazol-2-yl)-5- (1,3-thiazol-2- yloxy)benzamide ¹H NMR (500 MHz,CDCl₃): δ [ppm] = 8.56 (s, 1H), 8.11 (t, J = 1.5 Hz, 1H), 7.93 (dd, J =2.3, 1.5 Hz, 1H), 7.80-7.74 (m, 1H), 7.60 (dd, J = 8.0, 2.3 Hz, 1H),7.53 (d, J = 1.2 Hz, 1H), 7.24 (d, J = 3.8 Hz, 1H), 7.14 (d, J = 8.0 Hz,1H), 6.88 (d, J = 3.8 Hz, 1H), 6.42 (d, J= 7.1 Hz, 1H), 5.33 (p, J = 7.2Hz, 1H), 2.55 (s, 3H), 2.53 (d, J = 1.1 Hz, 3H), 1.64 (d, J = 7.0 Hz,3H). LCMS (Analytical Method D) Rt = 3.24 min, MS (ESIpos): m/z = 437.0(M + H)⁺.

Example 115N-[(1R)-1-(5-Chloropyridin-2-yl)ethyl]-3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)benzamide

Intermediate 5Q (115 mg, 0.34 mmol),(1R)-1-(5-chloropyridin-2-yl)ethanamine dihydrochloride (77 mg, 0.34mmol), DIPEA (0.23 mL, 1.35 mmol) and HATU (179 mg, 0.47 mmol) weredissolved in DMF (2.5 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The remaining crudematerial was purified by preparative HPLC (method 1, rt: 1.44 min) toafford the title compound 81 mg (50% yield).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.25 (s, 6 H) 1.53 (d, J=6.97 Hz, 3 H)3.18 (s, 3 H) 3.99 (s, 2 H) 5.19 (d, J=7.16 Hz, 1 H) 7.46 (d, J=8.29 Hz,1 H) 7.56-7.61 (m, 1 H) 7.62-7.66 (m, 1 H) 7.90 (dd, J=8.48, 2.45 Hz, 1H) 7.96 (t, J=1.41 Hz, 1 H) 8.01 (s, 1 H) 8.58 (d, J=2.07 Hz, 1 H) 9.10(d, J=7.54 Hz, 1 H).

Example 1163-(5-Chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5Q (115 mg, 0.34 mmol), Intermediate VI (77 mg, 0.34 mmol),DIPEA (0.23 mL, 1.35 mmol) and HATU (179 mg, 0.47 mmol) were dissolvedin DMF (2.5 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. The remaining crude material waspurified by preparative HPLC (method 1, rt: 1.41 min) to afford thetitle compound 97 mg (56% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.22-1.25 (m, 6 H) 1.61 (d, J=7.10 Hz,3 H) 3.17 (s, 3 H) 3.99 (s, 2 H) 5.30 (s, 1 H) 7.57-7.63 (m, 2 H) 7.93(t, J=1.39 Hz, 1 H) 8.01 (s, 1 H) 9.12 (s, 2 H) 9.18 (d, J=7.10 Hz, 1H).

Example 1173-(5-Chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]benzamide

Intermediate 5Q (115 mg, 0.34 mmol),(1R)-1-(5-methylpyrazin-2-yl)ethanamine hydrochloride (58 mg, 0.34mmol), DIPEA (0.23 mL, 1.35 mmol) and HATU (179 mg, 0.47 mmol) weredissolved in DMF (2.5 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The remaining crudematerial was purified by preparative HPLC (method 1, rt: 1.28 min) toafford the title compound 38 mg (23% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.23-1.25 (m, 6 H) 1.55 (d, J=7.10 Hz,3 H) 2.47 (s, 3 H) 3.17 (s, 3 H) 3.99 (s, 2 H) 5.19-5.28 (m, 1 H)7.56-7.59 (m, 1 H) 7.62 (d, J=1.52 Hz, 1 H) 7.95 (t, J=1.39 Hz, 1 H)8.00 (s, 1 H) 8.49 (d, J=0.76 Hz, 1 H) 8.56 (d, J=1.52 Hz, 1 H)9.08-9.14 (m, 1 H).

Example 118N-[(6-Methylpyridazin-3-yl)methyl]-3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-[5-(trifluoromethyl)-1,3-thiazol-2-yl]benzamide

Intermediate 5R (55% purity, 110 mg, 0.156 mmol),1-(6-methylpyridazin-3-yl)methanamine (19 mg, 0.156 mmol), DIPEA (0.11mL, 0.63 mmol) and HATU (83 mg, 0.22 mmol) were dissolved in DMF (2.5mL). The reaction mixture was stirred at RT until complete conversionand evaporated to dryness. The remaining crude material was purified bypreparative HPLC (method 1, rt: 1.19 min) to afford the title compound14 mg (18% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.29-1.43 (m, 2 H) 1.70 (br. s., 2 H)1.97-2.12 (m, 1 H) 2.60 (s, 3 H) 3.32-3.39 (m, 2 H) 3.89 (dd, J=11.12,3.28 Hz, 2 H) 4.00 (d, J=6.32 Hz, 2 H) 4.74 (d, J=5.81 Hz, 2 H) 7.54 (s,2 H) 7.62-7.74 (m, 2 H) 8.12 (t, J=1.39 Hz, 1 H) 8.51-8.64 (m, 1 H) 9.43(s, 1 H).

Example 1193-(5-Cyclobutyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

Intermediate 5S (53 mg, 0.14 mmol),1-(6-methylpyridazin-3-yl)methanamine (18 mg, 0.14 mmol), DIPEA (0.1 mL,0.57 mmol) and HATU (76 mg, 0.2 mmol) were dissolved in DMF (2.5 mL).The reaction mixture was stirred at RT until complete conversion andevaporated to dryness. The remaining crude material was purified bypreparative HPLC (method 1, rt: 1.22 min) to afford the title compound31 mg (45% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.30-1.43 (m, 2 H) 1.66-1.74 (m, 2 H)1.85-1.94 (m, 1 H) 1.96-2.07 (m, 2 H) 2.14 (d, J=2.53 Hz, 2 H) 2.43 (d,J=8.11 Hz, 2 H) 2.60 (s, 3 H) 3.35 (d, J=1.77 Hz, 2 H) 3.77-3.85 (m, 1H) 3.86-3.92 (m, 2 H) 3.96 (d, J=6.59 Hz, 2 H) 4.73 (d, J=5.83 Hz, 2 H)7.50-7.56 (m, 3 H) 7.56-7.59 (m, 1 H) 7.68 (d, J=0.76 Hz, 1 H) 7.99 (t,J=1.39 Hz, 1 H) 9.35-9.42 (m, 1 H).

Example 1203-(5-Cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5S (53 mg, 0.14 mmol), Intermediate VI (27 mg, 0.14 mmol),DIPEA (0.1 mL, 0.57 mmol) and HATU (76 mg, 0.2 mmol) were dissolved inDMF (2.5 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. The remaining crude material waspurified by preparative HPLC (method 1, rt: 1.47 min) to afford thetitle compound 40 mg (52% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.31-1.44 (m, 2 H) 1.61 (d, J=7.07 Hz,3 H) 1.67-1.75 (m, 2 H) 1.86-1.96 (m, 1 H) 1.97-2.08 (m, 2 H) 2.09-2.20(m, 2 H) 2.39-2.47 (m, 2 H) 3.35 (d, J=1.77 Hz, 2 H) 3.77-3.85 (m, 1 H)3.86-3.92 (m, 2 H) 3.97 (d, J=6.32 Hz, 2 H) 5.25-5.35 (m, 1 H) 7.49-7.53(m, 1 H) 7.55-7.58 (m, 1 H) 7.68 (d, J=1.01 Hz, 1 H) 7.94 (t, J=1.39 Hz,1 H) 9.12 (s, 2 H) 9.13-9.16 (m, 1 H).

Example 1213-(5-Cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

Intermediate 5T (150 mg, 0.42 mmol),(1R)-1-(5-methylpyrazin-2-yl)ethanamine dihydrochloride (105 mg, 0.5mmol), TEA (0.09 mL, 0.63 mmol) and HATU (175 mg, 0.46 mmol) weredissolved in DMSO (4.2 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The remaining crudematerial was purified by preparative HPLC (method 2, rt: 1.31 min) toafford the title compound 38 mg (19% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.55 (d, J=7.10 Hz, 3 H) 1.66-1.77 (m,1 H) 1.84-1.95 (m, 1 H) 2.03 (dd, J=10.65, 9.38 Hz, 2 H) 2.10-2.21 (m, 2H) 2.44 (dt, J=8.24, 3.11 Hz, 2 H) 2.47-2.49 (m, 3 H) 2.62-2.76 (m, 1 H)3.58 (dd, J=8.62, 5.58 Hz, 1 H) 3.68 (d, J=7.10 Hz, 1 H) 3.75-3.88 (m, 3H) 3.98-4.13 (m, 2 H) 5.24 (s, 1 H) 7.53-7.60 (m, 2 H) 7.68 (d, J=1.01Hz, 1 H) 7.97 (t, J=1.39 Hz, 1 H) 8.49 (d, J=0.76 Hz, 1 H) 8.57 (d,J=1.52 Hz, 1 H) 9.09 (d, J=7.35 Hz, 1 H).

Example 1223-(5-Cyclobutyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

Intermediate 5T (150 mg, 0.42 mmol),1-(6-methylpyridazin-3-yl)methanamine hydrochloride (93 mg, 0.58 mmol),TEA (0.09 mL, 0.63 mmol) and HATU (175 mg, 0.46 mmol) were dissolved inDMF (4.5 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. The remaining crude material waspurified by preparative HPLC (method 2, rt: 1.19 min) to afford thetitle compound 13 mg (6% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.70 (dd, J=13.31, 5.96 Hz, 1 H)1.84-1.95 (m, 1 H) 1.96-2.07 (m, 2 H) 2.09-2.20 (m, 2 H) 2.38-2.47 (m, 2H) 2.60 (s, 3 H) 2.64-2.74 (m, 1 H) 3.57 (dd, J=8.62, 5.58 Hz, 1 H) 3.67(q, J=7.69 Hz, 1 H) 3.74-3.85 (m, 3 H) 3.97-4.12 (m, 2 H) 4.73 (d,J=5.83 Hz, 2 H) 7.51-7.59 (m, 4 H) 7.68 (s, 1 H) 7.99 (s, 1 H) 9.39 (t,J=5.83 Hz, 1 H).

Example 1233-(5-Cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5T (150 mg, 0.42 mmol), Intermediate VI (104 mg, 0.46mmol), TEA (0.09 mL, 0.63 mmol) and HATU (175 mg, 0.46 mmol) weredissolved in DMSO (4.2 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The remaining crudematerial was purified by preparative HPLC (method 2, rt: 1.42 min) toafford the title compound 100 mg (45% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, J=7.10 Hz, 3 H) 1.66-1.76 (m,1 H) 1.84-1.94 (m, 1 H) 2.02 (td, J=9.06, 1.90 Hz, 2 H) 2.09-2.21 (m, 2H) 2.38-2.48 (m, 2 H) 2.63-2.74 (m, 1 H) 3.57 (dd, J=8.62, 5.58 Hz, 1 H)3.63-3.71 (m, 1 H) 3.74-3.85 (m, 3 H) 3.98-4.12 (m, 2 H) 5.30 (s, 1 H)7.53 (dd, J=2.28, 1.52 Hz, 1 H) 7.57 (dd, J=2.28, 1.52 Hz, 1 H) 7.68 (d,J=1.01 Hz, 1 H) 7.95 (t, J=1.39 Hz, 1 H) 9.12 (s, 2 H) 9.16 (d, J=7.10Hz, 1 H).

Example 1243-(5-Cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

Intermediate 5S (53 mg, 0.14 mmol),(1R)-1-(2-methylpyrimidin-5-yl)ethanamine (20 mg, 0.14 mmol), DIPEA (0.1mL, 0.57 mmol) and HATU (76 mg, 0.2 mmol) were dissolved in DMF (2.5mL). The reaction mixture was stirred at RT until complete conversionand evaporated to dryness. The remaining crude material was purified bypreparative HPLC (method 1, rt: 1.28 min) to afford the title compound21 mg (29% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.31-1.44 (m, 2 H) 1.55 (d, J=7.33 Hz,3 H) 1.66-1.75 (m, 2 H) 1.86-1.96 (m, 1 H) 1.96-2.07 (m, 2 H) 2.15 (s, 2H) 2.42 (s, 2 H) 2.59 (s, 3 H) 3.35 (d, J=1.77 Hz, 2 H) 3.77-3.85 (m, 1H) 3.85-3.92 (m, 2 H) 3.96 (d, J=6.32 Hz, 2 H) 5.13-5.23 (m, 1 H)7.48-7.51 (m, 1 H) 7.55 (dd, J=2.40, 1.64 Hz, 1 H) 7.68 (d, J=0.76 Hz, 1H) 7.93 (t, J=1.52 Hz, 1 H) 8.72 (s, 2 H) 9.01-9.06 (m, 1 H).

Example 1253-(5-Ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

Intermediate 5U (50 mg, 0.14 mmol),(1R)-1-(2-methylpyrimidin-5-yl)ethanamine (20 mg, 0.14 mmol), DIPEA (0.1mL, 0.58 mmol) and HATU (77 mg, 0.2 mmol) were dissolved in DMF (2.5mL). The reaction mixture was stirred at RT until complete conversionand evaporated to dryness. The remaining crude material was purified bypreparative HPLC (method 1, rt: 1.16 min) to afford the title compound23 mg (34% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.29 (t, J=7.48 Hz, 3 H) 1.37 (dd,J=12.55, 4.18 Hz, 2 H) 1.55 (d, J=7.10 Hz, 3 H) 1.65-1.76 (m, 2 H)1.96-2.10 (m, 1 H) 2.59 (s, 3 H) 2.84-2.95 (m, 2 H) 3.33-3.39 (m, 2 H)3.89 (dd, J=11.15, 3.04 Hz, 2 H) 3.96 (d, J=6.34 Hz, 2 H) 5.17 (t,J=7.22 Hz, 1 H) 7.47-7.51 (m, 1 H) 7.53-7.56 (m, 1 H) 7.67 (s, 1 H) 7.91(t, J=1.27 Hz, 1 H) 8.72 (s, 2 H) 9.04 (d, J=7.35 Hz, 1 H).

Example 126N-[(1R)-1-(2-Methylpyrimidin-5-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

Intermediate 5V (70 mg, 0.19 mmol),(1R)-1-(2-methylpyrimidin-5-yl)ethanamine (27 mg, 0.19 mmol), DIPEA(0.14 mL, 0.78 mmol) and HATU (103 mg, 0.27 mmol) were dissolved in DMF(2.5 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. The remaining crude material waspurified by preparative HPLC (method 1, rt: 1.23 min) to afford thetitle compound 11 mg (11% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.33 (d, J=6.84 Hz, 6 H) 1.37 (d,J=8.62 Hz, 2 H) 1.55 (d, J=7.10 Hz, 3 H) 1.70 (d, J=10.65 Hz, 2 H)1.97-2.10 (m, 1 H) 2.57-2.60 (m, 3 H) 3.24-3.30 (m, 1 H) 3.34-3.39 (m, 2H) 3.89 (dd, J=11.41, 2.28 Hz, 2 H) 3.96 (d, J=6.34 Hz, 2 H) 5.10-5.23(m, 1 H) 7.47-7.57 (m, 2 H) 7.68 (d, J=1.01 Hz, 1 H) 7.92 (t, J=1.27 Hz,1 H) 8.72 (s, 2 H) 8.99-9.09 (m, 1 H).

Example 1273-(5-Cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

Intermediate 5W (57 mg, 0.16 mmol),(1R)-1-(6-methylpyridazin-3-yl)ethanamine dihydrochloride (37 mg, 0.17mmol), TEA (0.03 mL, 0.24 mmol) and HATU (66 mg, 0.17 mmol) weredissolved in DMSO (1.6 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The remaining crudematerial was purified by column chromatography (silica gel, hexane/EEgradient) to afford the title compound 27 mg (36% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.56-1.69 (m, 5 H) 1.85-1.94 (m, 1 H)1.95-2.06 (m, 3 H) 2.09-2.21 (m, 2 H) 2.38-2.48 (m, 2 H) 2.59 (s, 3 H)3.48-3.58 (m, 2 H) 3.76-3.91 (m, 3 H) 4.76 (s, 1 H) 5.32-5.41 (m, 1 H)7.50-7.62 (m, 4 H) 7.68 (d, J=0.76 Hz, 1 H) 7.96 (t, J=1.39 Hz, 1 H)9.12 (d, J=7.33 Hz, 1 H).

Example 1283-(5-Ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

Intermediate 5X (62 mg, 0.19 mmol),(1R)-1-(6-methylpyridazin-3-yl)ethanamine dihydrochloride (43 mg, 0.21mmol), TEA (0.04 mL, 0.28 mmol) and HATU (78 mg, 0.21 mmol) weredissolved in DMSO (1.9 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The remaining crudematerial was purified by column chromatography (silica gel, hexane/EEgradient) to afford the title compound 12 mg (14% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.29 (t, J=7.48 Hz, 3 H) 1.55-1.69 (m,5 H) 2.00 (d, J=11.15 Hz, 2 H) 2.59 (s, 3 H) 2.85-2.96 (m, 2 H)3.48-3.58 (m, 2 H) 3.81-3.91 (m, 2 H) 4.76 (s, 1 H) 5.36 (t, J=7.22 Hz,1 H) 7.50-7.62 (m, 4 H) 7.67 (s, 1 H) 7.92-7.97 (m, 1 H) 9.13 (d, J=7.60Hz, 1 H).

Example 1293-(5-Ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5X (62 mg, 0.19 mmol), Intermediate VI (47 mg, 0.21 mmol),TEA (0.04 mL, 0.28 mmol) and HATU (78 mg, 0.21 mmol) were dissolved inDMSO (1.9 mL). The reaction mixture was stirred at RT until completeconversion and evaporated to dryness. The remaining crude material waspurified by column chromatography (silica gel, hexane/EE gradient) toafford the title compound 15 mg (16% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.29 (t, J=7.48 Hz, 3 H) 1.57-1.68 (m,5 H) 2.00 (dd, J=12.42, 2.53 Hz, 2 H) 2.90 (qd, J=7.48, 0.89 Hz, 2 H)3.47-3.57 (m, 2 H) 3.81-3.90 (m, 2 H) 4.71-4.81 (m, 1 H) 5.29 (t, J=7.10Hz, 1 H) 7.54 (dd, J=2.28, 1.52 Hz, 1 H) 7.57-7.61 (m, 1 H) 7.68 (t,J=1.01 Hz, 1 H) 7.93 (t, J=1.39 Hz, 1 H) 9.12 (s, 2 H) 9.15 (d, J=7.10Hz, 1 H).

Example 130N-[(1R)-1-(2-Methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol),(1R)-1-(2-methylpyrimidin-5-yl)ethanamine hydrochloride (96 mg, 0.55mmol), TEA (0.08 mL, 0.59 mmol) and HATU (1.79 g, 4.72 mmol) weredissolved in DMF (4.3 mL). The reaction mixture was stirred at 60° C.until complete conversion and evaporated to dryness. Crude material waspurified by preparative HPLC (method 1, rt: 0.98 min) to afford thetitle compound 87 mg (52% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.54 (d, J=7.10 Hz, 3 H) 1.95-2.05 (m,1 H) 2.25 (s, 1 H) 2.59 (s, 3 H) 3.77-3.93 (m, 4 H) 5.12-5.23 (m, 2 H)7.48 (dd, J=2.28, 1.52 Hz, 1 H) 7.50-7.53 (m, 1 H) 7.65 (d, J=1.01 Hz, 1H) 7.91 (t, J=1.39 Hz, 1 H) 8.72 (s, 2 H) 9.05 (d, J=7.60 Hz, 1 H).

Example 131N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[(6-methylpyridin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

Intermediate 5N (375 mg, 1.15 mmol),(1R)-1-(5-methylpyrazin-2-yl)ethanamine hydrochloride (219 mg, 1.26mmol), DIPEA (0.8 mL, 4.6 mmol) and HATU (612 mg, 1.61 mmol) weredissolved in DMF (13.3 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The crude material wasextracted three times with EE and evaporated to dryness again. Theremaining crude material was purified by preparative HPLC (method 1, rt:0.97 min) to afford the title compound 13 mg (2.5% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.53 (d, J=7.07 Hz, 3 H) 2.47 (s, 3 H)5.22 (s, 1 H) 7.37 (d, J=8.34 Hz, 1 H) 7.54 (d, J=2.78 Hz, 1 H)7.58-7.65 (m, 3 H) 8.13 (t, J=1.39 Hz, 1 H) 8.38 (d, J=2.78 Hz, 1 H)8.48 (s, 1 H) 8.55 (d, J=1.26 Hz, 1 H) 9.17 (d, J=7.58 Hz, 1 H).

Example 132N-[1-(3-Chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol), (+/−)1-(3-chloro-5-fluoropyridin-2-yl)ethanamine (96 mg, 0.55 mmol), TEA(0.08 mL, 0.59 mmol) and HATU (164 mg, 0.43 mmol) were dissolved in DMF(3.9 mL). The reaction mixture was stirred at 60° C. until completeconversion and evaporated to dryness. Crude material was purified bypreparative HPLC (method 1, rt: 1.28 min) to afford the title compound95 mg (52% yield) as a mixture of two diastereoisomers.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.49 (d, J=6.84 Hz, 3 H) 1.95-2.05 (m,1 H) 2.18-2.31 (m, 1 H) 3.75-3.94 (m, 4 H) 5.20 (d, J=1.52 Hz, 1 H) 5.54(t, J=6.97 Hz, 1 H) 7.51 (d, J=1.27 Hz, 2 H) 7.64 (d, J=1.27 Hz, 1 H)7.93 (q, J=1.44 Hz, 1 H) 8.09 (dd, J=8.62, 2.53 Hz, 1 H) 8.58 (d, J=2.79Hz, 1 H) 9.08 (d, J=7.10 Hz, 1 H).

Example 133N-[(6-Methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol),1-(6-methylpyridazin-3-yl)methanamine hydrochloride (88 mg, 0.55 mmol),TEA (0.08 mL, 0.59 mmol) and HATU (164 mg, 0.43 mmol) were dissolved inDMF (4.3 mL). The reaction mixture was stirred at 60° C. until completeconversion and evaporated to dryness. Crude material was purified bypreparative HPLC (method 1, rt: 0.91 min) to afford the title compound70 mg (42% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 2.03 (br. s., 1 H) 2.21-2.31 (m, 1 H)2.61 (s, 3 H) 3.77-3.94 (m, 4 H) 4.73 (d, J=5.83 Hz, 2 H) 5.16-5.23 (m,1 H) 7.53 (dt, J=6.72, 2.09 Hz, 2 H) 7.57 (s, 2 H) 7.64 (d, J=1.27 Hz, 1H) 7.98 (t, J=1.39 Hz, 1 H) 9.40 (t, J=5.83 Hz, 1 H).

Example 134N-[1-(5-Chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol), (+/−)1-(5-chloro-3-fluoropyridin-2-yl)ethanamine (96 mg, 0.55 mmol), TEA(0.08 mL, 0.59 mmol) and HATU (164 mg, 0.43 mmol) were dissolved in DMF(4.3 mL). The reaction mixture was stirred at 60° C. until completeconversion and evaporated to dryness. Crude material was purified bypreparative HPLC (method 1, rt: 1.28 min) to afford the title compound75 mg (41% yield) as a mixture of two diastereoisomers.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.51 (d, J=7.10 Hz, 3 H) 1.94-2.05 (m,1 H) 2.24 (s, 1 H) 3.77-3.93 (m, 4 H) 5.19 (d, J=1.52 Hz, 1 H) 5.42 (s,1 H) 7.49-7.53 (m, 2 H) 7.64 (d, J=1.27 Hz, 1 H) 7.93 (q, J=1.27 Hz, 1H) 8.06 (dd, J=9.89, 2.03 Hz, 1 H) 8.49 (d, J=1.52 Hz, 1 H) 9.10 (d,J=7.10 Hz, 1 H).

Example 1353-(5-Cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

Intermediate 5T (150 mg, 0.42 mmol),(1R)-1-(6-methylpyridazin-3-yl)ethanamine dihydrochloride (96 mg, 0.46mmol), TEA (0.09 mL, 0.63 mmol) and HATU (175 mg, 0.46 mmol) weredissolved in DMSO (4.2 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The remaining crudematerial was purified by preparative HPLC (method 2, rt: 1.24 min) toafford the title compound 57 mg (29% yield).

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.59 (d, J=7.10 Hz, 3 H) 1.71 (d,J=7.60 Hz, 1H) 1.91 (d, J=0.76 Hz, 1 H) 1.96-2.07 (m, 2 H) 2.09-2.20 (m,2 H) 2.38-2.48 (m, 2 H) 2.59 (s, 3 H) 2.68 (d, J=6.84 Hz, 1 H) 3.58 (dd,J=8.62, 5.58 Hz, 1 H) 3.63-3.72 (m, 1 H) 3.74-3.88 (m, 3 H) 3.98-4.12(m, 2 H) 5.37 (t, J=7.22 Hz, 1 H) 7.50-7.62 (m, 4 H) 7.68 (d, J=0.76 Hz,1 H) 7.97 (t, J=1.39 Hz, 1 H) 9.14 (d, J=7.60 Hz, 1 H).

Example 1363-(2-Methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

3-Bromo-5-(2-methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]benzamide

Intermediate 5Y (5.12 g, 18.6 mmol),(1R)-1-(2-methylpyrimidin-5-yl)ethanamine dihydrochloride (5.08 g, 24.2mmol), DIPEA (16.2 mL, 93 mmol) and HATU (7.78 g, 20.5 mmol) weredissolved in DMF (25 mL) at 60° C. Water and EE were added, the phasesseparated, the organic phase washed with water, dried (Na₂SO₄) andevaporated to dryness. The crude material was purified by columnchromatography (silica gel, hexane/EE gradient) to afford the titlecompound 5.45 g (74% yield).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.51 (d, J=7.16 Hz, 3 H) 2.59 (s, 3 H)3.30 (s, 3 H) 3.61-3.69 (m, 2 H) 4.13-4.20 (m, 2 H) 5.12 (s, 1 H) 7.34(s, 1 H) 7.43 (s, 1 H) 7.61 (s, 1 H) 8.69 (s, 2 H) 8.95 (d, J=7.16 Hz, 1H).

3-(2-Methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

3-Bromo-5-(2-methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]benzamide(5.3 g, 13.4 mmol), bis(pinacolato)diborane (6.83 g, 26.9 mmol) andpotassium acetate (4.62 g, 47 mmol) were dissolved in 1,4-dioxane andthe mixture degasse with nitrogen for 20 minutes at RT. Pd(dppf)Cl₂ (984mg, 1.34 mmol) was added and the reaction mixture was degassed foranother 5 minutes and then stirred at 90° C. for 16 hours. The reactionmixture was portioned between EE and water. The aqueous phase wasextracted with EE, the combined organics dried (Na₂SO₄) and concentratedin vacuo. Purification by column chromatography (silica gel, hexane/EEgradient) afforded the title compound 2.51 g (42% yield).

3-(2-Methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

3-(2-Methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(150 mg, 0.34 mmol) and 2-bromo-5-methyl-1,3-thiazole (91 mg, 0.51 mmol)were dissolved in 1M K₂CO₃ aqueous solution (0.84 mL) and THF.Pd(dppf)Cl₂.CH₂Cl₂ (42 mg, 0.05 mmol) was added and the reaction mixtureheated to reflux overnight. The reaction mixture was concentrated underreduced pressure. Crude material was purified by preparative HPLC(Method 1) to afford the title compound 80 mg (57% yield).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.54 (d, J=7.16 Hz, 3 H) 2.59 (s, 3 H)3.32 (s, 3 H) 3.69 (dd, J=5.18, 3.67 Hz, 2 H) 4.19-4.25 (m, 2 H) 5.17(t, J=7.16 Hz, 1 H) 7.50-7.56 (m, 2 H) 7.64 (d, J=1.32 Hz, 1 H) 7.91 (s,1 H) 8.72 (s, 2 H) 9.05 (d, J=7.54 Hz, 1 H).

Example 137 tert-Butyl4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate

To a solution of3-{[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoicacid (682 mg, 1.63 mmol), Intermediate VI (408 mg, 1.79 mmol) and DIPEA(1.14 mL, 6.52 mmol) in DCM (6 mL) was added T3P (1.43 mL, 2.44 mmol)and the resulting solution stirred for 2 h at RT. The reaction mixturewas diluted with DCM (6 mL) and washed with sodium bicarbonate. Theorganic phase was separated, dried (over MgSO₄) and concentrated invacuo. The crude material was purified by Biotage Isolera™chromatography (pre-packed SiO₂ column eluting with EtOAc) to give thetitle compound 130 mg (46% yield) as a colourless oil.

¹H NMR (250 MHz, CDCl3): δ [ppm]=8.93 (s, 2H), 7.83 (s, 1H), 7.58-7.47(m, 2H), 7.44-7.34 (m, 1H), 6.83 (d, J=6.7 Hz, 1H), 5.35 (p, J=8.0, 7.6Hz, 1H), 4.59 (dt, J=7.2, 3.6 Hz, 1H), 3.76-3.61 (m, 2H), 3.41-3.25 (m,2H), 2.53 (d, J=0.9 Hz, 3H), 2.01-1.85 (m, 2H), 1.82-1.70 (m, 5H), 1.46(s, 9H).

LCMS (Analytical Method D) Rt=5.13, MS (ESIpos) m/z=592 (M+H)⁺.

Example 1383-(5-Methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of tert-butyl4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate(100 mg, 0.169 mmol) in DCM (1 mL) was added TFA (0.13 mL, 1.69 mmol)and the reaction stirred at RT until gas evolution ceased. The reactionmixture was concentrated in vacuo and the residue taken up in DCM andneutralised with saturated NaHCO₃ solution. The organic phase wasseparated, dried (over MgSO₄) and concentrated in vacuo to give thetitle compound 72 mg (85% yield) as a white solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.95 (s, 2H), 7.89 (s, 1H),7.57-7.53 (m, 2H), 7.52 (d, J=1.1 Hz, 1H), 7.42 (d, J=1.5 Hz, 1H), 7.00(d, J=6.7 Hz, 1H), 5.37 (p, J=7.1 Hz, 1H), 4.73-4.69 (m, 1H), 3.34-3.26(m, 2H), 3.10-3.03 (m, 2H), 2.53 (d, J=0.9 Hz, 3H), 2.19-2.12 (m, 4H),2.03-1.97 (m, 2H), 1.72 (d, J=7.1 Hz, 3H).

LCMS (Analytical Method D) Rt=3.14, MS (ESIpos) m/z=491 (M+H)⁺.

Example 1393-[(1-Methylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamidehydrochloride (80 mg, 0.15 mmol) suspended in DCE (1 mL) was added 37%formaldehyde solution in water (0.045 mL, 0.61 mmol) and the resultingmixture stirred for 30 min. Sodium triacetoxyborohydride (38 mg, 0.18mmol) was added and the reaction mixture stirred for 16 h. LCMS (MethodA) indicated unreacted starting material. The reaction was retreatedwith 37% formaldehyde solution (1 mL) and 3 drops of acetic acid andstirred for 30 min. Sodium triacetoxyborohydride (38 mg, 0.18 mmol) wasadded and the mixture stirred for 8 h. LCMS (Method A) indicatedcomplete conversion to product. The organic solvent was removed underreduced pressure and the remaining aqueous basified to pH ˜8-9 andextracted into EtOAc (2 mL). The organic phase was separated, dried(over MgSO₄), concentrated and purified by preparative HPLC (Method A)to give the title compound 39.6 mg (52% yield) as a white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.93 (s, 2H), 7.83 (s, 1H),7.54-7.49 (m, 2H), 7.41-7.37 (m, 1H), 6.70 (d, J=6.5 Hz, 1H), 5.35 (p,J=7.0 Hz, 1H), 4.48-4.43 (m, 1H), 2.74-2.63 (m, 2H), 2.53 (d, J=0.9 Hz,3H), 2.34-2.25 (m, 5H), 2.07-2.01 (m, 2H), 2.00 (s, 0H), 1.90-1.81 (m,2H), 1.71 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method D) Rt=3.23, MS (ESIpos) m/z=506 (M+H)⁺.

Example 1403-(5-Methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a stirred solution of3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamidehydrochloride (80 mg, 50% purity, 0.076 mmol) in DCE (1 mL) was addedacetone (1 mL). After stirring at RT for 30 min, STAB (20 mg, 0.094mmol) was added and the reaction mixture stirred for a further 4 h. LCMS(Method A) indicated ˜20% conversion. A further portion of acetone (1mL) and STAB (20 mg, 0.094 mmol) were added and the reaction mixturestirred for 16 h at 40° C. LCMS (Method A) indicated ˜50% conversion.The reaction mixture was concentrated in vacuo and basified with 10 MNaOH to form a white precipitate that was extracted into EtOAc. Theorganic phase was concentrated in vacuo and purified by preparative HPLC(Method A) to give the title compound 20 mg (49% yield) as a tan powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.93 (s, 2H), 7.82 (t, J=1.4 Hz,1H), 7.53-7.49 (m, 2H), 7.41-7.36 (m, 1H), 6.76 (d, J=6.6 Hz, 1H), 5.35(t, J=7.0 Hz, 1H), 4.42 (dt, J=7.9, 4.0 Hz, 1H), 2.81-2.70 (m, 3H), 2.52(d, J=1.1 Hz, 3H), 2.40 (t, J=8.9 Hz, 2H), 2.07-2.00 (m, 2H), 1.87-1.77(m, 2H), 1.70 (d, J=7.2 Hz, 3H), 1.05 (d, J=6.6 Hz, 6H).

LCMS (Analytical Method D) Rt=3.36, MS (ESIpos) m/z=534 (M+H)⁺.

Example 1413-{[(3R)-1-Methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of methyl3-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate(143 mg, 0.32 mmol) in THF (1 mL) was added 1M lithium hydroxide (0.48mL) and stirred for 16 h at RT. The organic solvent was removed underreduced pressure and the aqueous phase acidified to pH 4 thenconcentrated to dryness. The reaction residue, [Intermediate VI (88 mg,0.39 mmol)] and DIPEA (0.23 mL, 1.29 mmol) were combined in DCM (1 mL)and T3P (50% in EtOAc, 0.14 mL, 0.48 mmol) was added and the resultingsolution stirred for 16 h at RT. The mixture was diluted with DCM (1mL), washed with brine (1 mL), dried (over Na₂SO₄) and concentrated invacuo to give a yellow oil. The crude material was purified bypreparative HPLC (Method A) to give the title compound 42 mg (26% yield)as a white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.95 (s, 2H), 7.86 (t, J=1.4 Hz,1H), 7.53 (d, J=1.2 Hz, 1H), 7.51 (dd, J=2.4, 1.5 Hz, 1H), 7.37-7.34 (m,1H), 7.28 (s, 1H), 6.74 (d, J=6.5 Hz, 1H), 5.37 (p, J=7.0 Hz, 1H),5.00-4.91 (m, 1H), 2.94-2.88 (m, 2H), 2.77 (dd, J=10.7, 5.7 Hz, 1H),2.55 (d, J=1.1 Hz, 3H), 2.45-2.35 (m, 5H), 2.07-1.98 (m, 1H), 1.72 (d,J=7.2 Hz, 3H).

LCMS (Analytical Method D) Rt=3.16, MS (ESIpos) m/z=492 (M+H)⁺.

Example 1423-{[(3S)-1-Methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To methyl3-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate(64 mg, 0.19 mmol) in THF was added 1 M lithium hydroxide (0.3 mL) andthe resulting solution stirred at RT for 4 h. The reaction mixture wasconcentrated in vacuo, the residue acidified with 2M HCl andconcentrated to dryness. The residue was dissolved in DCM andIntermediate VI (48 mg, 0.21 mmol), DIPEA (0.13 mL, 0.77 mmol) and HATU(110 mg, 0.29 mmol) were added and the mixture stirred at RT for 2 h.The reaction mixture was diluted with DCM (1 mL), washed with water (1mL) and dried (over MgSO₄) and concentrated in vacuo. The crude materialwas purified by preparative HPLC (Method A) to give the title compound23.9 mg (25% yield) as an off white solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm]=8.93 (s, 2H), 7.86 (t, J=1.4 Hz,1H), 7.51 (d, J=1.2 Hz, 1H), 7.49 (dd, J=2.3, 1.5 Hz, 1H), 7.37-7.32 (m,1H), 6.75 (d, J=6.6 Hz, 1H), 5.35 (p, J=7.0 Hz, 1H), 4.97-4.90 (m, 1H),2.93-2.84 (m, 2H), 2.75 (dd, J=10.8, 5.7 Hz, 1H), 2.53 (d, J=1.1 Hz,3H), 2.43-2.32 (m, 5H), 2.06-1.96 (m, 1H), 1.70 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method D) Rt=3.18 min, MS (ESIpos) m/z=492 (M+H)⁺.

Example 1433-[(1-Methylazetidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To methyl3-[(1-methylazetidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate (80mg, 0.25 mmol) in THF (1 mL) was added 1M lithium hydroxide solution(0.37 mL) and the resulting solution stirred at RT for 3 h. The reactionmixture was concentrated in vacuo and the residue acidified to pH 5 with1 M HCl then concentrated to dryness. The residue was dissolved in DCM(1 mL) and Intermediate VI (67 mg, 0.29 mmol), DIPEA (0.17 mL, 0.99mmol) and HATU (140 mg, 0.37 mmol) were added and the mixture stirred atRT for 2 h. The mixture was diluted with DCM (1 mL), washed with water(1 mL), dried (over MgSO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (Method A) to give the title compound 41.3mg (35% yield) as a white powder.

¹H NMR (500 MHz, CDCl₃): δ [ppm]=1.69 (d, 3H), 2.39 (s, 3H), 2.52 (d,3H), 3.11-3.18 (m, 2H), 3.78-3.85 (m, 2H), 4.82 (p, 1H), 5.34 (p, 1H),6.87 (d, 1H), 7.20-7.25 (m, 1H), 7.37 (dd, 1H), 7.49 (d, 1H), 7.85 (s,1H), 8.92 (s, 2H).

LCMS (Analytical Method F) Rt=2.03 min, MS (ESIpos) m/z=478 (M+H)⁺.

Example 1443-(5-Methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5D (540 mg, 1.98 mmol),(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine (415 mg, 2.17mmol), TEA (0.41 mL, 2.96 mmol) and HATU (826 mg, 2.17 mmol) weredissolved in DMSO (20 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The remaining crudematerial was purified by column chromatography (silica gel, hexane/EEgradient) to afford the title compound 600 mg (68% yield).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.61 (d, J=7.16 Hz, 3 H) 3.64 (t,J=2.35 Hz, 1 H) 4.95 (d, J=2.26 Hz, 2 H) 5.30 (t, J=7.06 Hz, 1 H)7.53-7.58 (m, 1 H) 7.61-7.64 (m, 1 H) 7.66 (d, J=1.13 Hz, 1 H) 7.97 (s,1 H) 9.12 (s, 2 H) 9.19 (d, J=7.16 Hz, 1 H).

Example 1453-(5-Methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5K (530 mg, 1.66 mmol),(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine (349 mg, 1.83mmol), TEA (0.35 mL, 2.49 mmol) and HATU (694 mg, 1.83 mmol) weredissolved in DMSO (17 mL). The reaction mixture was stirred at RT untilcomplete conversion and evaporated to dryness. The remaining crudematerial was purified by column chromatography (silica gel, hexane/EEgradient) to afford the title compound 600 mg (73% yield).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm] 1.54-1.70 (m, 5 H) 1.93-2.07 (m, 2 H)3.46-3.59 (m, 2 H) 3.80-3.91 (m, 2 H) 4.69-4.82 (m, 1 H) 5.29 (t, J=7.06Hz, 1 H) 7.51-7.55 (m, 1 H) 7.56-7.61 (m, 1 H) 7.64 (d, J=1.13 Hz, 1 H)7.91 (t, J=1.32 Hz, 1 H) 9.12 (s, 2 H) 9.16 (d, J=7.16 Hz, 1 H).

In analogy to the procedure described for Example 1, the followingexamples were prepared using HATU and the appropriate carboxylic acidand amine starting materials.

Ex. Structure Name Analytical Data 146

tert-butyl 6-[3-(5- methyl-1,3- thiazol-2-yl)-5- ({(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl}carbamoyl) phenoxy]-2-azaspiro[3.3]heptane- 2-carboxylate ¹H NMR (500 MHz, MeOD): δ [ppm] 9.01(s, 2H), 7.90 (t, 1H), 7.56 (d, 1H), 7.50 (dd, 1H), 7.35 (dd, 1H), 5.34(q, 1H), 4.74 (m, 1H), 4.01 (s, 2H), 3.92 (s, 2H), 2.80 (dd, 2H), 2.54(d, 3H), 2.37- 2.29 (m, 2H), 1.70 (d, 3H), 1.43 (s, 9H). LCMS(Analytical Method D) Rt = 5.05 min, MS (ESIpos): 604 (M + H)⁺. 147

3-(5-methyl-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3-yloxy]-N-{(1R)-1- [5- (trifluoromethyl) pyrazin-2- yl]ethyl}benzamide ¹HNMR (250 MHz, MeOD): δ [ppm] 9.03-8.94 (m, 1H), 8.86 (s, 1H), 7.92 (t,1H), 7.58 (dd, 1H), 7.55 (d, 1H), 7.45 (dd, 1H), 5.42 (q, 1H), 5.14(ddt, 1H), 4.09- 3.81 (m, 4H), 3.72 (ddd, 1H), 2.53 (d, 3H), 2.42-2.05(m, 2H), 1.68 (d, 3H). LCMS (Analytical Method D) Rt = 4.44 min, MS(ESIpos): m/z = 479 (M + H)⁺. 148

3-(5-methyl-1,3- thiazol-2-yl)-5- (oxetan-3-yloxy)- N-{(1R)-1-[6-(trifluoromethyl) pyridin-3- yl]ethyl}benzamide ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 8.76 (d, J = 1.7 Hz, 1H), 7.89-7.84 (m, 2H), 7.65(d, J = 8.1 Hz, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.34 (dd, J = 2.4, 1.4Hz, 1H), 7.19-7.14 (m, 1H), 6.78 (d, J = 7.0 Hz, 1H), 5.35 (m, 1H),5.31-5.25 (m, 1H), 5.00 (t, J = 6.7 Hz, 2H), 4.74 (dd, J = 7.4, 5.2 Hz,2H), 2.52 (d, J = 1.0 Hz, 3H), 1.64 (d, J = 7.1 Hz, 3H). LCMS(Analytical Method D) Rt = 3.36 min, MS (ESIpos): m/z = 464 (M + H)⁺.149

3-(1- azabicyclo[2.2.2] oct-4-yloxy)-5-(5- methyl-1,3- thiazol-3-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 8.85 (s, 2H), 7.90 (t, J = 1.4 Hz, 1H),7.48-7.45 (m, 1H), 7.43 (d, J = 1.1 Hz, 1H), 7.39- 7.34 (m, 1H), 6.85(d, J = 6.6 Hz, 1H), 5.27 (m, 1H), 2.95-2.88 (m, 6H), 2.45 (d, J = 0.9Hz, 3H), 1.76-1.69 (m, 6H), 1.62 (d, J = 7.2 Hz, 3H). LCMS (AnalyticalMethod F) Rt = 2.15 min, MS (ESIpos): m/z = 518 (M + H)⁺. 150

3-[(1- acetylpiperidin-4- yl)oxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR(250 MHz, DMSO-d6): δ [ppm] 9.09 (s, 2H), 8.91 (d, J = 7.1 Hz, 1H), 7.92(t, J = 1.4 Hz, 1H), 7.65-7.56 (m, 2H), 7.56- 7.50 (m, 1H), 5.32 (m,1H), 4.76 (tt, J = 7.5, 3.8 Hz, 1H), 3.91- 3.65 (m, 2H), 3.38 (ddd, J =13.1, 8.3, 3.7 Hz, 2H), 2.09- 1.88 (m, 5H), 1.75-1.55 (m, 5H). LCMS(Analytical Method D) Rt = 4.23 min, MS (ESIpos): m/z = 534 (M + H)⁺.151

N-{(1R)-1-[2- (difluoromethyl) pyrimidin-5- yl]ethyl}-3-(5- methyl-1,3-thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3- yloxy]benzamide ¹H NMR (500MHz, Chloroform-d): δ [ppm] 8.90 (s, 2H), 7.85 (s, 1H), 7.54-7.48 (m,2H), 7.36 (s, 1H), 6.78-6.53 (m, 2H), 5.35 (m, 1H), 5.07-5.03 (m, 1H),4.05-3.96 (m, 3H), 3.91 (td, J = 8.4, 4.3 Hz, 1H), 2.53 (s, 3H),2.33-2.22 (m, 1H), 2.20-2.11 (m, 1H), 1.70 (d, J = 7.1 Hz, 3H). LCMS(Analytical Method F) Rt = 2.95 min, MS (ESIpos): m/z = 461 (M + H)⁺.152

N-{(1R)-1-[2- (difluoromethyl) pyrimidin-5- yl]ethyl}-3-(5- methyl-1,3-thiazol-2-yl)-5- (oxetan-3- yloxy)benzamide ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 8.88 (s, 2H), 7.85 (s, 1H), 7.51 (s, 1H), 7.36(s, 1H), 7.16 (s, 1H), 6.79-6.53 (m, 2H), 5.38-5.25 (m, 2H), 5.01 (t, J= 6.7 Hz, 2H), 4.75 (dd, J = 7.1, 5.3 Hz, 2H), 2.53 (s, 3H), 1.69 (d, J= 7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 2.93 min, MS (ESIpos):m/z = 447 (M + H)⁺. 153

N-{(1R)-1-[2- (difluoromethyl) pyrimidin-5- yl]ethyl}-3-(5- methyl-1,3-thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3- yloxy]benzamide ¹H NMR (500MHz, Chloroform-d): δ [ppm] 8.89 (s, 2H), 7.85 (s, 1H), 7.54-7.47 (m,2H), 7.38- 7.33 (m, 1H), 6.78-6.53 (m, 2H), 5.34 (m, 1H), 5.08-5.01 (m,1H), 4.05-3.96 (m, 3H), 3.91 (td, J = 8.4, 4.3 Hz, 1H), 2.53 (d, J = 1.0Hz, 3H), 2.32- 2.21 (m, 1H), 2.19-2.10 (m, 1H), 1.70 (d, J = 7.1 Hz,3H). LCMS (Analytical Method F) Rt = 2.94 min, MS (ESIpos): m/z = 461(M + H)⁺. 154

N-{(1R)-1-[2- (difluoromethyl) pyrimidin-5- yl]ethyl}-3-(5- methyl-1,3-thiazol-2-yl)-5- (tetrahydro-2H- pyran-4- yloxy)benzamide ¹H NMR (500MHz, Chloroform-d): δ [ppm] 8.88 (s, 2H), 7.81 (t, J = 1.2 Hz, 1H), 7.51(dd, J = 2.3, 1.5 Hz, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.41-7.37 (m, 1H),6.80 (d, J = 6.8 Hz, 1H), 6.65 (t, J = 54.5 Hz, 1H), 5.33 (m, 1H), 4.60(tt, J = 7.9, 3.9 Hz, 1H), 4.00-3.93 (m, 2H), 3.57 (ddd, J = 11.5, 8.6,2.7 Hz, 2H), 2.52 (d, J = 1.0 Hz, 3H), 2.07-2.00 (m, 2H), 1.84- 1.73 (m,2H), 1.68 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 3.09 min,MS (ESIpos): m/z = 474 (M + H)⁺. 155

3-{[(3S)-1- methylpiperidin-3- yl]oxy}-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.89 (s, 2H),7.81 (t, J = 1.4 Hz, 1H), 7.52 (dd, J = 2.3, 1.5 Hz, 1H), 7.45 (d, J =1.2 Hz, 1H), 7.40-7.36 (m, 1H), 6.98 (d, J = 6.7 Hz, 1H), 5.32 (m, 1H),4.48 (dq, J = 7.2, 3.6 Hz, 1H), 2.74 (d, J = 10.2 Hz, 1H), 2.48 (d, J =1.1 Hz, 4H), 2.37-2.33 (m, 1H), 2.26 (s, 4H), 1.90-1.79 (m, 2H), 1.65(d, J = 7.2 Hz, 3H), 1.62-1.54 (m, 2H). LCMS (Analytical Method D) Rt =3.28 min, MS (ESIpos): m/z = 506 (M + H)⁺. 156

3-[(3- methyloxetan-3- yl)oxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 8.90 (s, 2H), 7.83 (t, J = 1.4 Hz, 1H),7.48 (d, J = 1.2 Hz, 1H), 7.25 (dd, J = 2.4, 1.4 Hz, 1H), 7.06 (dd, J =2.3, 1.5 Hz, 1H), 6.93 (d, J = 6.6 Hz, 1H), 5.32 (m, 1H), 4.91 (dd, J =6.5, 1.9 Hz, 2H), 4.62 (dd, J = 6.6, 3.4 Hz, 2H), 2.51 (d, J = 1.1 Hz,3H), 1.75 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H). LCMS (Analytical Method D)Rt = 4.32 min, MS (ESIpos): m/z = 478 (M + H)⁺. 157

3-(5-methyl-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3-yloxy]-N-{(1R)-1- [6- (trifluoromethyl) pyridin-3- yl]ethyl}benzamide ¹HNMR (500 MHz, Chloroform-d): δ [ppm] 8.81 (s, 1H), 8.02-7.82 (m, 2H),7.69 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 11.9 Hz, 2H), 7.40 (s, 1H), 6.63(d, J = 6.7 Hz, 1H), 5.40 (m, 1H), 5.20-4.96 (m, 1H), 4.10-3.98 (m, 3H),3.93 (td, J = 8.4, 4.3 Hz, 1H), 2.56 (s, 3H), 2.29 (td, J = 14.2, 8.3Hz, 1H), 2.18 (dt, J = 11.9, 4.9 Hz, 1H), 1.70 (d, J = 7.1 Hz, 3H). LCMS(Analytical Method F) Rt = 3.42 min, MS (ESIpos): m/z = 478.0 (M + H)⁺.158

3-{[(3R)-1- methylpiperidin-3- yl]oxy}-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.88 (s, 2H),7.79 (s, 1H), 7.53-7.48 (m, 1H), 7.46- 7.42 (m, 1H), 7.36 (d, J = 1.5Hz, 1H), 6.99 (d, J = 6.1 Hz, 1H), 5.31 (m, 1H), 4.47 (dt, J = 7.1, 3.5Hz, 1H), 2.73 (d, J = 10.2 Hz, 1H), 2.50-2.43 (m, 4H), 2.34 (s, 1H),2.26 (s, 4H), 1.89-1.78 (m, 2H), 1.64 (d, J = 7.2 Hz, 3H), 1.62-1.51 (m,2H). LCMS (Analytical Method D) Rt = 3.32 min, MS (ESIpos): m/z = 506(M + H)⁺. 159

3-(5-methyl-1,3- thiazol-2-yl)-5-[2- (1H-1,2,4-triazol- 1-yl)ethoxy]-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 8.25 (s, 1H), 7.95 (m,2H), 7.54 (d, J = 1.2 Hz, 1H), 7.50-7.46 (m, 1H), 7.36 (s, 1H), 6.71 (s,1H), 5.36 (m, 1H), 4.67-4.56 (m, 2H), 4.45 (dd, J = 7.1, 3.0 Hz, 2H),2.54 (d, J = 1.1 Hz, 3H), 1.73 (d, J = 7.2 Hz, 3H). LCMS (AnalyticalMethod F) Rt = 2.87 min, MS (ESIpos): m/z = 505.1 (M + H)⁺. 160

3-(5-methyl-1,3- thiazol-2-yl)-5-[2- (1H-1,2,4-triazol- 1-yl)ethoxy]-N-{(1R)-1-[6- (trifluoromethyl) pyridin-3- yl]ethyl}benzamide ¹H NMR (500MHz, Chloroform-d): δ [ppm] 8.79 (d, J = 1.6 Hz, 1H), 8.27 (s, 1H), 7.97(s, 1H), 7.92- 7.83 (m, 2H), 7.67 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 1.2Hz, 1H), 7.50-7.45 (m, 1H), 7.35 (s, 1H), 6.61 (d, J = 6.8 Hz, 1H), 5.38(m, 1H), 4.61 (t, J = 4.9 Hz, 2H), 4.48-4.41 (m, 2H), 2.53 (d, J = 1.1Hz, 3H), 1.68 (d, J = 7.1 Hz, 3H) LCMS (Analytical Method F) Rt = 2.96min, MS (ESIpos): m/z = 503.1 (M + H)⁺. 161

3-(5-methyl-1,3- thiazol-2-yl)-5- (oxetan-3-yloxy)- N-{(1R)-1-[6-(trifluoromethyl) pyridazin-3- yl]ethyl}benzamide ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 7.90 (t, J = 1.4 Hz, 1H), 7.83 (d, J = 8.7 Hz,1H), 7.74 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.52 (d, J =1.2 Hz, 1H), 7.39 (dd, J = 2.4, 1.4 Hz, 1H), 7.21 (dd, J = 2.4, 1.5 Hz,1H), 5.59 (m, 1H), 5.36-5.28 (m, 1H), 5.06-4.98 (m, 2H), 4.80- 4.73 (m,2H), 2.53 (d, J = 1.1 Hz, 3H), 1.76 (d, J = 7.0 Hz, 3H). LCMS(Analytical Method D) Rt = 4.12 min, MS (ESIpos): m/z = 465 (M + H)⁺.

Intermediate 63 was formed as a mixture of two trans isomers. ChiralPurification (Method 2) provided Example 162 (Trans Isomer 1) andExample 163 (Trans Isomer 2)

Example 162 Trans Isomer 1;3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral Purification (Method 2) on 189 mg of Intermediate 63 gave 72 mgof the title compound.

SFC Chiral Analysis (Method 2): 100% e.e., Rt=1.25 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.76 (s, 1H), 7.50(s, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 6.95 (d, J=6.4 Hz, 1H), 5.35 (m,1H), 4.43 (qd, J=6.2, 3.3 Hz, 1H), 4.02 (qd, J=6.4, 3.3 Hz, 1H), 2.52(s, 3H), 1.72 (s, 3H), 1.27 (d, J=6.3 Hz, 3H), 1.25 (d, J=6.5 Hz, 3H).

LCMS (Analytical Method D) Rt=4.14 min, MS (ESIpos) m/z=481 (M+H)⁺.

Example 163 Trans Isomer 2;3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral Purification (Method 2) on 189 mg of Intermediate 63 gave 77.2 mgof the title compound.

SFC Chiral Analysis (Method 2): 99.4% e.e., Rt=1.42 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.80 (s, 1H),7.54-7.49 (m, 1H), 7.47 (s, 1H), 7.38-7.33 (m, 1H), 6.82 (d, J=6.5 Hz,1H), 5.35 (m, 1H), 4.47 (qd, J=6.3, 3.3 Hz, 1H), 4.03 (qd, J=6.4, 3.3Hz, 1H), 2.53 (d, J=0.9 Hz, 3H), 1.71 (d, J=7.2 Hz, 3H), 1.29 (d, J=6.3Hz, 3H), 1.27 (d, J=6.5 Hz, 3H).

LCMS (Analytical Method D) Rt=4.15 min, MS (ESIpos) m/z=481 (M+H)⁺.

In analogy to the procedure described for Example 7, the followingexamples were prepared using T3P and the appropriate carboxylic acid andamine starting materials.

Ex. Structure Name Analytical Data 164

N-{[(1R)-1-[6- (difluoromethyl) pyridin-3-yl]ethyl}-3- (5-methyl-1,3-thiazol-2-yl)-5- (oxetan-3- yloxy)benzamide ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 8.71 (d, J = 1.6 Hz, 1H), 7.90-7.80 (m, 2H), 7.63(d, J = 8.1 Hz, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.37 (dd, J = 2.4, 1.4Hz, 1H), 7.20-7.18 (m, 1H), 6.76- 6.49 (m, 2H), 5.41-5.28 (m, 2H),5.05-4.99 (m, 2H), 4.77 (dd, J = 7.4, 5.1 Hz, 2H), 2.54 (d, J = 1.0 Hz,3H), 1.67 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 3.02 min,MS (ESIpos): m/z = 446.0 (M + H)⁺. 165

3-{[trans-3- (dimethylamino) cyclobutyl]oxy}-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H),7.84 (t, J = 1.4 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 2.3,1.5 Hz, 1H), 7.30-7.25 (m, 3H), 6.68 (d, J = 6.6 Hz, 1H), 5.35 (m, 1H),4.85 (tt, J = 6.7, 3.4 Hz, 1H), 2.93 (ddd, J = 13.7, 7.6, 6.1 Hz, 1H),2.53 (d, J = 1.1 Hz, 3H), 2.46- 2.38 (m, 2H), 2.34-2.27 (m, 2H), 2.16(s, 6H), 1.71 (d, J = 7.2 Hz, 3H). LCMS (Analytical Method F) Rt = 2.17min, MS (ESIpos): m/z = 506.2 (M + H)⁺. 166

3-(5-methyl-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3-yloxy]-N-{[2- (trifluoromethyl) pyrimidin-5- yl]methyl}benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.86 (t, J = 1.4 Hz, 1H),7.53-7.49 (m, 2H), 7.39 (dd, J = 2.3, 1.6 Hz, 1H), 6.95 (t, J = 5.8 Hz,1H), 5.06 (ddt, J = 5.9, 4.0, 1.9 Hz, 1H), 4.72 (d, J = 6.1 Hz, 2H),4.06-3.97 (m, 3H), 3.92 (td, J = 8.4, 4.3 Hz, 1H), 2.53 (d, J = 1.1 Hz,3H), 2.28 (dtd, J = 14.4, 8.4, 6.1 Hz, 1H), 2.21-2.12 (m, 1H). LCMS(Analytical Method F) Rt = 3.23 min, MS (ESIpos): m/z = 465.1 (M + H)⁺.167

3-(5-methyl-1,3- thiazol-2-yl)-5- (oxetan-3-yloxy)- N-{[2-(trifluoromethyl) pyrimidin-5- yl]methyl}benzamide ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.88 (t, J = 1.4 Hz, 1H), 7.51 (d,J = 1.2 Hz, 1H), 7.39 (dd, J = 2.4, 1.4 Hz, 1H), 7.20 (dd, J = 2.4, 1.5Hz, 1H), 6.92 (s, 1H), 5.33 (m, 1H), 5.04 (t, J = 7.0 Hz, 2H), 4.77 (dd,J = 8.0, 5.0 Hz, 2H), 4.73 (d, J = 6.0 Hz, 2H), 2.53 (d, J = 1.1 Hz,3H). LCMS (Analytical Method D) Rt = 4.10 min, MS (ESIpos): m/z = 451.0(M + H)⁺. 168

3-[(3R)-1- azabicyclo[2.2.2] oct-3-yloxy]-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.97 (s, 2H),7.85 (s, 1H), 7.52 (dd, J = 4.5, 1.6 Hz, 2H), 7.38 (s, 1H), 6.85 (s,1H), 5.37 (m, 1H), 4.61-4.55 (m, 1H), 3.52- 3.43 (m, 1H), 3.09-3.00 (m,1H), 2.99-2.83 (m, 4H), 2.53 (d, J = 1.1 Hz, 3H), 2.28-2.21 (m, 1H),2.09-2.01 (m, 1H), 1.84-1.75 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H), 1.66 (s,1H), 1.53-1.42 (m, 1H). LCMS (Analytical Method F) Rt = 2.22 min, MS(ESIpos): m/z = 518.1 (M + H)⁺. 169

3-(5-ethyl-1,3- thiazol-2-yl)-5- (oxetan-3-yloxy)- N-{(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87 (s, 1H), 7.56 (s, 1H), 7.39(dd, J = 2.3, 1.4 Hz, 1H), 7.20-7.16 (m, 1H), 6.60 (d, J = 6.4 Hz, 1H),5.39-5.29 (m, 2H), 5.03 (t, J = 6.7 Hz, 2H), 4.77 (dd, J = 7.4, 5.1 Hz,2H), 2.92 (q, J = 7.5 Hz, 2H), 1.72 (d, J = 7.2 Hz, 3H), 1.37 (t, J =7.5 Hz, 3H). LCMS (Analytical Method F) Rt = 4.42 min, MS (ESIpos): m/z= 479.05 (M + H)⁺. 170

3-[(6- methylpyridazin-3- yl)oxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 8.06 (s, 1H), 7.80 (s,1H), 7.67 (s, 1H), 7.47 (s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.15 (d, J =8.9 Hz, 1H), 5.37-5.30 (m, 1H), 2.63 (s, 3H), 2.50 (s, 3H), 1.65 (s,3H). LCMS (Analytical Method D) Rt = 4.16 min, MS (ESIpos): m/z = 501.1(M + H)⁺. 171

N-{(1R)-1-[6- (difluoromethyl) pyridin-3-yl]ethyl}-3- (5-methyl-1,3-thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3- yloxy]benzamide ¹H NMR (500MHz, Chloroform-d): δ [ppm] 8.71 (d, J = 1.8 Hz, 1H), 7.91-7.81 (m, 2H),7.63 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.50 (dd, J = 2.3,1.5 Hz, 1H), 7.43-7.31 (m, 1H), 6.76- 6.51 (m, 2H), 5.37 (m, 1H), 5.12-5.00 (m, 1H), 4.07-3.99 (m, 3H), 3.91 (td, J = 8.4, 4.3 Hz, 1H), 2.54(d, J = 1.0 Hz, 3H), 2.34-2.22 (m, 1H), 2.20-2.12 (m, 1H), 1.67 (d, J =7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 3.13 min, MS (ESIpos): m/z= 460.1 (M + H)⁺. 172

3-[(3R)-1- azabicyclo[2.2.2] oct-3-yloxy]-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[6- (trifluoromethyl) pyridin-3-yl]ethyl}benzamide ¹H NMR (500 MHz, DMSO-d6): δ [ppm] = 9.14 (d, J =7.4, 1H), 8.82 (d, J = 1.7, 1H), 8.08 (dd, J = 8.2, 1.8, 1H), 7.92-7.88(m, 2H), 7.64 (d, J = 1.2, 1H), 7.51-7.49 (m, 1H), 7.49-7.46 (m, 1H),5.28 (dq, J = 7.0, 1H), 4.60 (dt, J = 6.8, 2.8, 1H), 3.26 (ddd, J =14.1, 7.9, 1.6, 1H), 2.84-2.60 (m, 5H), 2.51 (s, 3H), 2.10-2.03 (m, 1H),1.89- 1.79 (m, 1H), 1.71-1.61 (m, 1H), 1.61-1.52 (m, 4H), 1.39-1.29 (m,1H) LCMS (Analytical Method F) Rt = 2.30 min, MS (ESIpos): m/z = 517.1(M + H)⁺. 173

3-[(3S)-1- azabicyclo[2.2.2] oct-3-yloxy]-5-(5- ethyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹HNMR (500 MHz, Chloroform-d): δ [ppm] 8.96 (s, 2H), 7.83 (s, 1H), 7.57(s, 1H), 7.53 (dd, J = 2.3, 1.5 Hz, 1H), 7.39-7.36 (m, 1H), 6.64 (d, J =6.6 Hz, 1H), 5.38 (m, 1H), 4.57-4.49 (m, 1H), 3.35 (ddd, J = 14.3, 8.0,1.9 Hz, 1H), 3.06-2.76 (m, 7H), 2.24-2.16 (m, 1H), 2.06- 1.94 (m, 1H),1.85-1.77 (m, 1H), 1.74 (d, J = 7.2 Hz, 3H), 1.65- 1.57 (m, 1H),1.48-1.42 (m, 1H), 1.39 (t, J = 7.5 Hz, 3H). LCMS (Analytical Method D)Rt = 3.60 min, MS (ESIpos): m/z = 532.0 (M + H)⁺. 174

3-[(3R)-1- azabicyclo[2.2.2] oct-3-yloxy]-5-(5- ethyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹HNMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.81 (s, 1H), 7.55(s, 1H), 7.50 (dd, J = 2.2, 1.5 Hz, 1H), 7.37-7.33 (m, 1H), 6.63 (d, J =6.5 Hz, 1H), 5.36 (m, 1H), 4.58-4.46 (m, 1H), 3.34 (ddd, J = 14.3, 7.9,1.8 Hz, 1H), 3.03-2.74 (m, 7H), 2.22-2.14 (m, 1H), 2.05- 1.93 (m, 1H),1.80-1.74 (m, 1H), 1.72 (d, J = 7.2 Hz, 3H), 1.62- 1.54 (m, 1H),1.47-1.39 (m, 1H), 1.37 (t, J = 7.5 Hz, 3H). LCMS (Analytical Method D)Rt = 3.61 min, MS (ESIpos): m/z = 532.1 (M + H)⁺. 175

3-[(3S)-1- azabicyclo[2.2.2] oct-3-yloxy]-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[6- (trifluoromethyl) pyridin-3-yl]ethyl}benzamide ¹H NMR (500 MHz, DMSO-d6): δ [ppm] = 9.13 (d, J =7.4, 1H), 8.82 (d, J = 1.6, 1H), 8.08 (dd, J = 8.1, 1.8, 1H), 7.93-7.86(m, 2H), 7.64 (d, J = 1.2, 1H), 7.49 (dt, J = 11.1, 2.2, 2H), 5.28 (dq,J = 7.2, 1H), 4.60 (dt, J = 6.7, 2.8, 1H), 3.30- 3.21 (m, 1H), 2.85-2.60(m, 5H), 2.51 (s, 3H), 2.07 (q, J = 2.8, 1H), 1.84 (dddd, J = 15.5, 7.3,5.3, 3.4, 1H), 1.66 (ddt, J = 13.3, 9.4, 4.9, 1H), 1.63-1.53 (m, 4H),1.40- 1.30 (m, 1H) LCMS (Analytical Method F) Rt = 2.28 min, MS(ESIpos): m/z = 517.2 (M + H)⁺. 176

3-[(5-methyl- 1,3,4-thiadiazol-2- yl)oxy]-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[6- (trifluoromethyl) pyridin-3-yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.78 (d, J =1.8 Hz, 1H), 8.14 (t, J = 1.3 Hz, 1H), 7.95 (dd, J = 2.3, 1.5 Hz, 1H),7.89 (dd, J = 8.1, 2.0 Hz, 1H), 7.82-7.76 (m, 1H), 7.67 (d, J = 8.1 Hz,1H), 7.53 (d, J = 1.1 Hz, 1H), 6.76 (d, J = 7.0 Hz, 1H), 5.38 (m, 1H),2.68 (s, 3H), 2.53 (d, J = 1.0 Hz, 3H), 1.68 (d, J = 7.1 Hz, 3H). LCMS(Analytical Method D) Rt = 4.40 min, MS (ESIpos): m/z = 506.0 (M + H)⁺.177

3-[(2R)-1,4-dioxan-2- ylmethoxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[6- (trifluoromethyl) pyridin-3- yl]ethyl}benzamide ¹H NMR (500MHz, Chloroform-d): δ [ppm] 8.81-8.74 (m, 1H), 7.88 (s, 2H), 7.66 (d, J= 8.1 Hz, 1H), 7.55 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 6.59 (d, J =6.9 Hz, 1H), 5.38 (m, 1H), 4.13-4.06 (m, 1H), 4.06-3.98 (m, 2H), 3.88(td, J = 11.8, 2.3 Hz, 2H), 3.82 (td, J = 11.7, 11.1, 2.6 Hz, 1H),3.78-3.72 (m, 1H), 3.67 (td, J = 11.3, 3.1 Hz, 1H), 3.59- 3.51 (m, 1H),2.53 (s, 3H), 1.67 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method F) Rt =3.36 min, MS (ESIpos): m/z = 508.1 (M + H)⁺. 178

3-[(2R)-1,4-dioxan-2- ylmethoxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 7.90 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H),7.73 (d, J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 7.45 (d, J = 7.3Hz, 1H), 7.42 (s, 1H), 5.60 (m, 1H), 4.14-4.07 (m, 1H), 4.06- 3.97 (m,2H), 3.94-3.85 (m, 2H), 3.82 (td, J = 11.7, 11.1, 2.6 Hz, 1H), 3.78-3.73(m, 1H), 3.68 (td, J = 11.2, 3.2 Hz, 1H), 3.57 (dd, J = 11.3, 9.9 Hz,1H), 2.53 (s, 3H), 1.76 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method F)Rt = 3.14 min, MS (ESIpos): m/z = 509.1 (M + H)⁺. 179

3-[(2R)-1,4-dioxan-2- ylmethoxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl]ethyl} benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87 (s, 1H), 7.56 (d, J= 2.0 Hz, 1H), 7.53- 7.48 (m, 1H), 7.43-7.34 (m, 1H), 6.64 (d, J = 6.5Hz, 1H), 5.36 (m, 1H), 4.13-4.07 (m, 1H), 4.06- 3.96 (m, 2H), 3.88 (td,J = 12.3, 11.8, 2.2 Hz, 2H), 3.82 (td, J = 11.7, 11.1, 2.6 Hz, 1H),3.78- 3.71 (m, 1H), 3.67 (td, J = 11.2, 3.1 Hz, 1H), 3.56 (dd, J = 11.4,9.7 Hz, 1H), 2.53 (s, 3H), 1.71 (d, J = 7.1 Hz, 3H). LCMS (AnalyticalMethod F) Rt = 3.28 min, MS (ESIpos): m/z = 509 (M + H)⁺. 180

3-[(2S)-1,4-dioxan- 2-ylmethoxy]-5-(5- methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6- (trifluoromethyl)pyridin- 3-yl]ethyl}benzamide ¹H NMR (500MHz, Chloroform-d): δ [ppm] 8.78 (s, 1H), 7.93-7.85 (m, 2H), 7.66 (d, J= 8.1 Hz, 1H), 7.53 (d, J = 11.1 Hz, 2H), 7.41 (s, 1H), 6.65 (d, J = 6.8Hz, 1H), 5.38 (m, 1H), 4.12-4.06 (m, 1H), 4.06- 3.96 (m, 2H), 3.88 (td,J = 12.1, 2.3 Hz, 2H), 3.81 (td, J = 11.7, 11.2, 2.6 Hz, 1H), 3.78-3.70(m, 1H), 3.67 (td, J = 11.3, 3.1 Hz, 1H), 3.59-3.50 (m, 1H), 2.53 (s,3H), 1.67 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 3.36 min,MS (ESIpos): m/z = 508 (M + H)⁺. 181

3-[(2S)-1,4-dioxan- 2-ylmethoxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87 (s, 1H), 7.55 (dd, J= 2.2, 1.4 Hz, 1H), 7.53-7.49 (m, 1H), 7.41-7.37 (m, 1H), 6.69 (d, J =6.6 Hz, 1H), 5.36 (m, 1H), 4.13-4.06 (m, 1H), 4.05-3.97 (m, 2H), 3.88(td, J = 12.0, 2.4 Hz, 2H), 3.81 (td, J = 11.7, 11.1, 2.6 Hz, 1H), 3.78-3.71 (m, 1H), 3.67 (td, J = 11.2, 3.1 Hz, 1H), 3.56 (dd, J = 11.3, 10.0Hz, 1H), 2.57-2.46 (m, 3H), 1.71 (d, J = 7.1 Hz, 3H). LCMS (AnalyticalMethod F) Rt = 3.28 min, MS (ESIpos): m/z = 509 (M + H)⁺. 182

3-[(2S)-1,4-dioxan- 2-ylmethoxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 7.92 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H),7.74 (d, J = 8.7 Hz, 1H), 7.63-7.57 (m, 1H), 7.55- 7.50 (m, 1H), 7.48(d, J = 7.3 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 5.60 (m, 1H), 4.13-4.07(m, 1H), 4.07- 3.96 (m, 2H), 3.93-3.85 (m, 2H), 3.82 (td, J = 11.7,11.1, 2.6 Hz, 1H), 3.78-3.72 (m, 1H), 3.68 (td, J = 11.2, 3.1 Hz, 1H),3.57 (dd, J = 11.4, 9.8 Hz, 1H), 2.53 (s, 3H), 1.76 (d, J = 7.0 Hz, 3H).LCMS (Analytical Method F) Rt = 3.14 min, MS (ESIpos): m/z = 509 (M +H)⁺. 183

Trans Isomer 1; 3- {[3-hydroxybutan- 2-yl]oxy}-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.87 (t, J =1.3 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H),7.60-7.59 (m, 1H), 7.52 (d, J = 1.1 Hz, 1H), 7.50- 7.46 (m, 1H),7.43-7.41 (m, 1H), 5.60 (m, 1H), 4.52-4.47 (m, 1H), 4.08-4.03 (m, 1H),2.53 (d, J = 1.0 Hz, 3H), 2.00 (d, J = 4.9 Hz, 1H), 1.76 (d, J = 7.0 Hz,3H), 1.30 (d, J = 6.3 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H). LCMS(Analytical Method F) Rt = 3.07 min, MS (ESIpos): m/z = 481 (M + H)⁺.184

Trans Isomer 1; 3- (5-chloro-1,3- thiazol-2-yl)-5-{[3- hydroxybutan-2-yl]oxy}-N-{(1R)-1- [2-(trifluoromethyl) pyrimidin-5-yl]ethyl} benzamide¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.77 (t, J = 1.4Hz, 1H), 7.67 (s, 1H), 7.50 (dd, J = 2.4, 1.5 Hz, 1H), 7.41 (dd, J =2.4, 1.5 Hz, 1H), 6.57 (d, J = 6.5 Hz, 1H), 5.36 (m, 1H), 4.48 (qd, J =6.3, 3.3 Hz, 1H), 4.09-4.00 (m, 1H), 1.98 (d, J = 5.0 Hz, 1H), 1.73 (d,J = 7.2 Hz, 3H), 1.31 (d, J = 6.3 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H).LCMS (Analytical Method D) Rt = 4.39 min, MS (ESIpos): m/z = 501 (M +H)⁺. 185

Cis Isomer 1; 3-(5- chloro-1,3-thiazol- 2-yl)-5-{[3- hydroxybutan-2-yl]oxy}-N-{(1R)-1- [2-(trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide¹H NMR (500 MHz, DMSO-d6) δ [ppm] 9.16 (d, J = 7.1 Hz, 1H), 9.11 (s,2H), 8.00 (s, 1H), 7.91- 7.88 (m, 1H), 7.60-7.55 (m, 2H), 5.35-5.23 (m,1H), 4.84 (d, J = 4.8 Hz, 1H), 4.49-4.39 (m, 1H), 3.81-3.73 (m, 1H),1.61 (d, J = 7.1 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.11 (d, J = 6.4 Hz,3H). LCMS (Analytical Method F) Rt = 3.56 min, MS (ESIpos): m/z = 501.1(M + H)⁺. 186

Trans Isomer 1; 3- (5-chloro-1,3- thiazol-2-yl)-5-{[3- hydroxybutan-2-yl]oxy}-N-{(1R)-1- [6-(trifluoromethyl) pyridin-3-yl]ethyl} benzamide ¹HNMR (500 MHz, Chloroform-d): δ [ppm] 8.79 (d, J = 1.9 Hz, 1H), 7.89 (dd,J = 8.1, 2.2 Hz, 1H), 7.77 (d, J = 1.4 Hz, 1H), 7.70- 7.66 (m, 2H), 7.51(dd, J = 2.4, 1.5 Hz, 1H), 7.43 (dd, J = 2.3, 1.5 Hz, 1H), 6.50 (d, J =7.0 Hz, 1H), 5.38 (m, 1H), 4.48 (qd, J = 6.3, 3.4 Hz, 1H), 4.09-4.01 (m,1H), 1.94 (d, J = 4.9 Hz, 1H), 1.69 (d, J = 7.1 Hz, 3H), 1.31 (d, J =6.3 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H). LCMS (Analytical Method D) Rt =4.46 min, MS (ESIpos): m/z = 499.95 (M + H)⁺. 187

Cis Isomer 2; 3-(5- chloro-1,3-thiazol- 2-yl)-5-{[3- hydroxybutan-2-yl]oxy}-N-{(1R)-1- [2-(trifluoromethyl) pyrimidin-5-yl]ethyl} benzamide¹H NMR (500 MHz, Chloroform-d) δ 8.94 (s, 2H), 7.77 (t, 1H), 7.67 (s,1H), 7.51-7.49 (m, 1H), 7.42- 7.41 (m, 1H), 6.66 (d, J = 6.6 Hz, 1H),5.36 (p, J = 7.0 Hz, 1H), 4.31 (p, J = 6.2 Hz, 1H), 3.88 (p, J = 6.5 Hz,1H), 2.43 (s, 1H), 1.73 (d, J = 7.2 Hz, 3H), 1.29 (dd, J = 11.5, 6.3 Hz,6H). LCMS (Analytical Method F) Rt = 3.54 min, MS (ESIpos): m/z = 501(M + H)⁺. 188

Trans Isomer 2; 3- (5-chloro-1,3- thiazol-2-yl)-5-{[3- hydroxybutan-2-yl]oxy}-N-{(1R)-1- [2-(trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.76 (t, J = 1.4Hz, 1H), 7.67 (s, 1H), 7.50 (dd, J = 2.4, 1.5 Hz, 1H), 7.41 (dd, J =2.4, 1.5 Hz, 1H), 6.58 (d, J = 6.6 Hz, 1H), 5.36 (m, 1H), 4.47 (qd, J =6.3, 3.4 Hz, 1H), 4.09- 3.96 (m, 1H), 1.98 (d, J = 4.9 Hz, 1H), 1.73 (d,J = 7.2 Hz, 3H), 1.31 (d, J = 6.3 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H).LCMS (Analytical Method D) Rt = 4.38 min, MS (ESIpos): m/z = 501 (M +H)⁺. 189

Trans Isomer 2; 3- (5-chloro-1,3- thiazol-2-yl)-5-{[3- hydroxybutan-2-yl]oxy}-N-{(1R)-1- [6- (trifluoromethyl) pyridin-3-yl]ethyl} benzamide¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.78 (d, J = 1.9 Hz, 1H), 7.88(dd, J = 8.1, 2.1 Hz, 1H), 7.77 (t, J = 1.4 Hz, 1H), 7.69- 7.65 (m, 2H),7.50 (dd, J = 2.4, 1.5 Hz, 1H), 7.44-7.38 (m, 1H), 6.51 (d, J = 6.9 Hz,1H), 5.38 (m, 1H), 4.47 (qd, J = 6.3, 3.4 Hz, 1H), 4.09-4.01 (m, 1H),1.96 (d, J = 4.9 Hz, 1H), 1.68 (d, J = 7.1 Hz, 3H), 1.31 (d, J = 6.3 Hz,3H), 1.27 (d, J = 6.5 Hz, 3H). LCMS (Analytical Method D) Rt = 4.46 min,MS (ESIpos): m/z = 499.95 (M + H)⁺.

Example 190 tert-Butyl(3R)-3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate,as a mixture of diastereoisomers

To a solution of Intermediate 5AF (200 mg, 0.44 mmol), Intermediate VI(121 mg, 0.53 mmol) and DIPEA (0.231 mL, 1.33 mmol) in DCM (1 mL) wasadded T3P (50% solution in EtOAc, 0.198 mL, 0.66 mmol) and the resultingsolution stirred at RT for 16 h. LCMS analysis indicated incompleteconsumption of starting material. HATU (50 mg, 0.13 mmol) was added andthe mixture stirred at RT for 2 h then diluted with DCM (1 mL) andwashed with water (1 mL). The organic phase was dried (MgSO₄), filteredand concentrated at reduced pressure. Purification by Biotage Isolera™chromatography (eluting with 0-80% EtOAc in heptane on a pre-packedKP-SiO₂ column) gave a colourless oil that was freeze-dried to give 195mg (71% yield) of the title compound as white powder.

¹H NMR (250 MHz, DMSO-d6): δ [ppm] 9.08 (s, 2H), 8.92 (d, J=7.1 Hz, 1H),7.94 (t, J=1.4 Hz, 1H), 7.65-7.47 (m, 3H), 5.33 (m, 1H), 4.53 (d, J=3.1Hz, 1H), 3.68-3.23 (m, 4H), 2.07-1.59 (m, 6H), 1.60-1.41 (m, 1H), 1.30(d, J=2.4 Hz, 9H).

LCMS (Analytical Method F) Rt=4.27 min, MS (ESIpos): m/z=592 (M+H)⁺.

In analogy to the procedure described for Example 190, the followingexamples were prepared using both T3P and HATU with the appropriatecarboxylic acid and amine starting materials.

Ex. Structure Name Analytical Data 191

3-(but-2-yn-1- yloxy)-N-[(1R)- 1-(6- methylpyridazin- 3- yl)ethyl]-5-(5-methyl- 1,3-thiazol-2-yl) benzamide ¹H NMR (500 MHz, Chloroform-d): δ[ppm] 7.94 (t, J = 1.4 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.60 (dd, J =2.4, 1.5 Hz, 1H), 7.52-7.46 (m, 2H), 7.41 (d, J = 8.6 Hz, 1H), 7.32 (d,J = 8.6 Hz, 1H), 5.46 (m, 1H), 4.73 (q, J = 2.3 Hz, 2H), 2.70 (s, 3H),2.51 (d, J = 1.1 Hz, 3H), 1.86 (t, J = 2.3 Hz, 3H), 1.68 (d, J = 6.9 Hz,3H). LCMS (Analytical Method D) Rt = 3.93 min, MS (ESIpos): m/z = 407(M + H)⁺. 192

3-[(3S)-1- azabicyclo[2.2.2] oct-3-yloxy]-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl] ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.81 (t,J = 1.3 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.50-7.48 (m, 1H), 7.36- 7.33(m, 1H), 6.65 (d, J = 6.5 Hz, 1H), 5.36 (m, 1H), 4.54-4.48 (m, 1H),3.37-3.29 (m, 1H), 3.03- 2.94 (m, 1H), 2.93-2.75 (m, 4H), 2.54 (d, J =1.0 Hz, 3H), 2.21- 2.16 (m, 1H), 2.02-1.93 (m, 1H), 1.80-1.74 (m, 1H),1.72 (d, J = 7.2 Hz, 3H), 1.63-1.55 (m, 1H), 1.45-1.37 (m, 1H). LCMS(Analytical Method F) Rt = 2.15 min, MS (ESIpos): m/z = 518.1 (M + H)⁺.

Examples 193 to 200 were prepared using T3P and the appropriatecarboxylic acid and amine starting materials. The isomeric mixtures wereseparated by the given methods into single isomers.

Example 193 (Enantiomer 1) and Example 194 (Enantiomer 2)3-(5-Methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide,Formed as a mixture of 2 enantiomers

Intermediate 5F (40 mg, 0.14 mmol),1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethanamine (38 mg, 0.17mmol) and DIPEA (0.12 mL, 0.69 mmol) were dissolved in DCM (2 mL). T3P(0.16 mL, 0.28 mmol, 50% in EtOAc) was added and the reaction mixturestirred at RT for 2 h. The reaction mixture washed with saturated NaHCO₃(3 mL) and the aqueous layer further extracted with DCM (2×2 mL). Thecrude material was purified by Biotage Isolera™ chromatography (elutingwith 10-70% EtOAc in heptane on a 10 g pre-packed KP-SiO₂ column) togive 31 mg (48% yield) of the title compound as a colourless gum.

¹H NMR (500 MHz, CDCl3): δ [ppm] 7.88 (t, J=1.4 Hz, 1H), 7.53 (d, J=1.2Hz, 1H), 7.40 (dd, J=2.4, 1.4 Hz, 1H), 7.22 (dd, J=2.4, 1.5 Hz, 1H),6.93 (d, J=7.4 Hz, 1H), 5.74 (m, 1H), 5.34 (m, 1H), 5.07-5.02 (m, 2H),4.78 (ddd, J=7.4, 5.0, 2.8 Hz, 2H), 2.54 (d, J=1.1 Hz, 3H), 1.91 (d,J=7.0 Hz, 3H).

LCMS (Analytical Method F) Rt=3.37 min, MS (ESIpos): m/z=471.1 (M+H)⁺.

Example 193: Enantiomer 1;3-(5-Methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

SFC Chiral Purification (Method 3) was performed on 28.7 mg ofEnantiomer 1 (Example 193) and Enantiomer 2 (Example 194) mixture togive 8.9 mg of the title compound.

SFC Chiral Analysis (Method 3): 100% e.e. Rt=2.21 min.

¹H NMR (500 MHz, CDCl3): δ [ppm] 7.87 (s, 1H), 7.53 (d, J=1.1 Hz, 1H),7.42-7.39 (m, 1H), 7.23-7.21 (m, 1H), 6.87 (d, J=7.5 Hz, 1H), 5.78-5.71(m, 1H), 5.34 (t, J=5.4 Hz, 1H), 5.04 (t, J=6.7 Hz, 2H), 4.78 (t, J=7.6Hz, 2H), 2.54 (d, J=1.1 Hz, 3H), 1.91 (d, J=7.0 Hz, 3H).

LCMS (Analytical Method D) Rt=4.39 min, MS (ESIpos): m/z=471.1 (M+H)⁺.

Example 194: Enantiomer 2;3-(5-Methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

SFC Chiral Purification (Method 3) was performed on 28.7 mg ofEnantiomer 1 (Example 193) and Enantiomer 2 (Example 194) mixture togive 11.7 mg of the title compound.

SFC Chiral Analysis (Method 3): 99.2% e.e. Rt=2.53 min.

¹H NMR (500 MHz, CDCl3): δ [ppm] 7.88 (s, 1H), 7.53 (s, 1H), 7.40 (s,1H), 7.22 (s, 1H), 6.91-6.85 (m, 1H), 5.78-5.71 (m, 1H), 5.37-5.31 (m,1H), 5.04 (t, J=6.7 Hz, 2H), 4.81-4.76 (m, 2H), 2.54 (s, 3H), 1.91 (d,J=7.1 Hz, 3H).

LCMS (Analytical Method D) Rt=4.40 min, MS (ESIpos): m/z=471.0 (M+H)⁺.

Example 195 (Enantiomer 1) and Example 196 (Enantiomer 2)3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide,Formed as a mixture of 2 enantiomers

Intermediate 5K (96 mg, 0.3 mmol),1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethanamine (84 mg, 0.36mmol) and DIPEA (0.261 mL, 1.5 mmol) were dissolved in DCM (3 mL). T3P(0.35 mL, 0.6 mmol, 50% in EtOAc) was added and the reaction mixturestirred at RT for 2 h. The reaction mixture washed with saturated NaHCO₃(3 mL) and the aqueous layer further extracted with DCM (2×2 mL). Thecombined organics were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was triturated with Et₂O to give112 mg (75% yield) of the title compound as white powder.

¹H NMR (500 MHz, CDCl3): δ [ppm] 7.84 (d, J=1.4 Hz, 1H), 7.60-7.57 (m,1H), 7.53 (d, J=1.1 Hz, 1H), 7.45-7.42 (m, 1H), 6.89 (d, J=7.4 Hz, 1H),5.74 (m, 1H), 4.65 (dq, J=7.7, 3.8 Hz, 1H), 4.03-3.96 (m, 2H), 3.61(ddd, J=11.6, 8.3, 3.2 Hz, 2H), 2.54 (d, J=1.0 Hz, 3H), 2.11-2.03 (m,2H), 1.91 (d, J=7.0 Hz, 3H), 1.82 (dtd, J=12.4, 8.1, 3.6 Hz, 2H).

LCMS (Analytical Method F) Rt=3.64 min, MS (ESIpos): m/z=499.1 (M+H)⁺.

Example 195: Enantiomer 1;3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

SFC Chiral Purification (Method 3) was performed on 112 mg of Enantiomer1 (Example 195) and Enantiomer 2 (Example 196) mixture to give 47.8 mgof the title compound.

SFC Chiral Analysis (Method 3): 100% e.e. Rt=2.21 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.84 (s, 1H), 7.60-7.57 (m, 1H),7.53 (d, J=1.1 Hz, 1H), 7.45-7.41 (m, 1H), 6.87 (d, J=7.1 Hz, 1H), 5.74(m, 1H), 4.70-4.61 (m, 1H), 4.03-3.96 (m, 2H), 3.61 (ddd, J=11.6, 8.3,3.2 Hz, 2H), 2.54 (d, J=1.1 Hz, 3H), 2.12-2.03 (m, 2H), 1.91 (d, J=7.0Hz, 3H), 1.86-1.77 (m, 2H).

LCMS (Analytical Method D) Rt=4.62 min, MS (ESIpos): m/z=499.1 (M+H)⁺.

Example 196: Enantiomer 2;3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

SFC Chiral Purification (Method 3) was performed on 112 mg of Enantiomer1 (Example 195) and Enantiomer 2 (Example 196) mixture to give 49.6 mgof the title compound.

SFC Chiral Analysis (Method 3): 100% e.e. Rt=2.70 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.85 (s, 1H), 7.59-7.57 (m, 1H),7.53 (d, J=1.2 Hz, 1H), 7.45-7.42 (m, 1H), 6.89 (d, J=7.0 Hz, 1H), 5.74(m, 1H), 4.71-4.62 (m, 1H), 4.04-3.94 (m, 2H), 3.61 (ddd, J=11.7, 8.4,3.2 Hz, 2H), 2.54 (d, J=1.1 Hz, 3H), 2.11-2.03 (m, 2H), 1.91 (d, J=7.0Hz, 3H), 1.87-1.78 (m, 2H).

LCMS (Analytical Method D) Rt=4.62 min, MS (ESIpos): m/z=499.2 (M+H)⁺.

Example 197 (Diastereoisomer 1) and Example 198 (Diastereoisomer 2)3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide,Formed as a Mixture of 2 Diastereoisomers

Intermediate 5B (92 mg, 0.3 mmol),1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethanamine (84 mg, 0.36mmol) and DIPEA (0.261 mL, 1.5 mmol) were dissolved in DCM (3 mL). T3P(0.35 mL, 0.6 mmol, 50% in EtOAc) was added and the reaction mixturestirred at RT for 2 h. The reaction mixture washed with saturated NaHCO₃(3 mL) and the aqueous layer further extracted with DCM (2×2 mL). Thecombined organics were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified by Biotage Isolera™chromatography (eluting with 10-70% EtOAc in heptane on a 10 gpre-packed KP-SiO₂ column) to give 86.1 mg (59% yield) of the titlecompound as white powder.

¹H NMR (500 MHz, CDCl3): δ [ppm] 7.86 (s, 1H), 7.54 (dd, J=2.3, 1.5 Hz,1H), 7.52 (d, J=1.1 Hz, 1H), 7.39 (q, J=2.2 Hz, 1H), 6.91 (d, J=7.3 Hz,1H), 5.74 (m, 1H), 5.13-5.03 (m, 1H), 4.07-3.97 (m, 3H), 3.92 (td,J=8.4, 4.2 Hz, 1H), 2.54 (d, J=1.0 Hz, 3H), 2.34-2.23 (m, 1H), 2.23-2.14(m, 1H), 1.91 (d, J=7.0 Hz, 3H).

LCMS (Analytical Method F) Rt=3.49 min, MS (ESIpos): m/z=485 (M+H)⁺.

Example 197: Diastereoisomer 1;3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

SFC Chiral Purification (Method 3) was performed on 86 mg ofDiastereoisomer 1 (Example 197) and Diastereoisomer 2 (Example 198)mixture to give 34.6 mg of the title compound.

SFC Chiral Analysis (Method 3): 100% e.e. Rt=2.39 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.87 (s, 1H), 7.60-7.50 (m, 2H),7.40 (s, 1H), 6.88 (d, J=6.6 Hz, 1H), 5.78-5.70 (m, 1H), 5.10-5.06 (m,1H), 4.06-3.98 (m, 3H), 3.93 (td, J=8.4, 4.3 Hz, 1H), 2.54 (s, 3H), 2.29(td, J=14.4, 8.4 Hz, 1H), 2.21-2.14 (m, 1H), 1.91 (d, J=7.0 Hz, 3H).

LCMS (Analytical Method D) Rt=4.49 min, MS (ESIpos): m/z=485 (M+H)⁺.

Example 198: Diastereoisomer 2;3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

SFC Chiral Purification (Method 3) was performed on 86 mg ofDiastereoisomer 1 (Example 197) and Diastereoisomer 2 (Example 198)mixture to give 36.9 mg of the title compound.

SFC Chiral Analysis (Method 3): 99.8% e.e. Rt=2.75 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.87 (s, 1H), 7.58-7.51 (m, 2H),7.40 (s, 1H), 6.88 (d, J=6.6 Hz, 1H), 5.81-5.69 (m, 1H), 5.08 (d, J=1.9Hz, 1H), 4.07-3.99 (m, 2H), 3.93 (td, J=8.3, 4.2 Hz, 1H), 2.54 (s, 3H),2.37-2.23 (m, 1H), 2.23-2.09 (m, 1H), 1.91 (d, J=7.0 Hz, 3H).

LCMS (Analytical Method D) Rt=4.49 min, MS (ESIpos): m/z=485 (M+H)⁺.

Example 199 (Diastereoisomer 1) and Example 200 (Diastereoisomer 2)3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide,Formed as a Mixture of 2 Diastereoisomers

Intermediate 5C (61 mg, 0.2 mmol),115-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethanamine (56 mg, 0.24mmol) and DIPEA (0.174 mL, 1 mmol) were dissolved in DCM (3 mL). T3P(0.234 mL, 0.4 mmol, 50% in EtOAc) was added and the reaction mixturestirred at RT for 2 h. The reaction mixture washed with saturated NaHCO₃(3 mL) and the aqueous layer further extracted with DCM (2×2 mL). Thecombined organics were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified by Biotage Isolera™chromatography (eluting with 20-80% EtOAc in heptane on a 10 gpre-packed KP-SiO₂ column) to give 41.1 mg (42% yield) of the titlecompound as an off-white solid.

¹H NMR (500 MHz, CDCl3): δ [ppm] 8.00 (s, 1H), 7.56 (s, 1H), 7.53 (s,1H), 7.43 (s, 1H), 7.05 (s, 1H), 5.75 (m, 1H), 5.08 (d, J=1.9 Hz, 1H),4.09-3.97 (m, 3H), 3.93 (td, J=8.4, 4.3 Hz, 1H), 2.55 (d, J=0.9 Hz, 3H),2.30 (td, J=14.3, 8.3 Hz, 1H), 2.24-2.13 (m, 1H), 1.92 (d, J=7.0 Hz,3H).

LCMS (Analytical Method D) Rt=4.43 min, MS (ESIpos): m/z=485.95 (M+H)⁺.

Example 199: Diastereoisomer 1;3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

SFC Chiral Purification (Method 3) was performed on 41 mg ofDiastereoisomer 1 (Example 199) and Diastereoisomer 2 (Example 200)mixture to give 13.1 mg of the title compound.

SFC Chiral Analysis (Method 3): 100% e.e. Rt=1.74 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.86 (s, 1H), 7.56-7.53 (m, 1H),7.53-7.52 (m, 1H), 7.41-7.38 (m, 1H), 6.90 (d, J=7.2 Hz, 1H), 5.74 (m,1H), 5.10-5.05 (m, 1H), 4.07-3.98 (m, 3H), 3.93 (td, J=8.4, 4.3 Hz, 1H),2.54 (s, 3H), 2.33-2.25 (m, 1H), 2.21-2.14 (m, 1H), 1.91 (d, J=7.0 Hz,3H).

LCMS (Analytical Method D) Rt=4.45 min, MS (ESIpos): m/z=485.05 (M+H)⁺.

Example 200: Diastereoisomer 2;3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

SFC Chiral Purification (Method 3) was performed on 41 mg ofDiastereoisomer 1 (Example 199) and Diastereoisomer 2 (Example 200)mixture to give 16.1 mg of the title compound.

SFC Chiral Analysis (Method 3): 100% e.e. Rt=2.81 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.86 (s, 1H), 7.54 (s, 1H), 7.53(s, 1H), 7.42-7.38 (m, 1H), 6.89 (d, J=7.1 Hz, 1H), 5.74 (m, 1H),5.11-5.03 (m, 1H), 4.06-3.99 (m, 3H), 3.93 (td, J=8.4, 4.3 Hz, 1H), 2.54(s, 3H), 2.35-2.24 (m, 1H), 2.22-2.14 (m, 1H), 1.91 (d, J=7.0 Hz, 3H).

LCMS (Analytical Method D) Rt=4.45 min, MS (ESIpos): m/z=485.0 (M+H)⁺.

Example 2013-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

To a solution of Intermediate 41 (178 mg, 0.30 mmol) in DCM (5 mL) wasadded TFA (0.23 mL, 3.0 mmol) and the resulting mixture stirred at RTfor 16 h. The reaction was quenched with 1M NaOH (5 mL), and the layersseparated. The aqueous layer was extracted with DCM (2×5 mL), and thecombined organics were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified by Biotage Isolera™chromatography (silica gel, eluting with heptanes-EtOAc, 1:4 to 0:1followed by EtOAc-MeOH, 1:0 to 4:1). The product containing fractionswere concentrated and the residue freeze-dried from MeCN/water to give101.3 mg (69% yield) of the title compound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.86 (t, J=1.4 Hz, 1H), 7.82 (d,J=8.7 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.58 (dd, J=2.3, 1.5 Hz, 1H),7.52 (d, J=1.2 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 7.43-7.40 (m, 1H), 5.60(m, 1H), 4.53 (tt, J=8.0, 3.8 Hz, 1H), 3.19-3.10 (m, 2H), 2.80-2.71 (m,2H), 2.53 (d, J=1.1 Hz, 3H), 2.09-1.99 (m, 2H), 1.76 (d, J=7.0 Hz, 3H),1.74-1.65 (m, 2H).

LCMS (Analytical Method F) Rt=2.02 min, MS (ESIpos): m/z=492.2 (M+H)⁺.

In analogy to the procedure described for Example 201, the followingexamples were prepared using TFA and the appropriate N-Boc-protectedamine starting materials.

Ex. Structure Name Analytical Data 202

3-(2- azaspiro[3.3] hept- 6-yloxy)-5-(5- methyl-1,3- thiazol-2- yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide ¹H NMR(500 MHz, DMSO-d6): δ [ppm] 9.22 (d, J = 7.1 Hz, 1H), 9.11 (s, 2H), 7.93(s, 1H), 7.66- 7.62 (m, 1H), 7.41 (d, J = 10.2 Hz, 2H), 5.29 (p, J = 7.0Hz, 1H), 4.78 (m, 1H), 4.03 (s, 2H), 3.93 (s, 2H), 3.17 (s, 3H), 2.81(dd, J = 12.4, 6.8 Hz, 2H), 2.30 (dd, J = 13.2, 6.6 Hz, 2H), 1.61 (d, J= 7.1 Hz, 3H). LCMS (Analytical Method D) Rt = 3.20 min, MS (ESIpos):m/z = 504 (M + H)⁺. 203

3-(5-methyl- 1,3-thiazol-2- yl)-5-[(3S)- pyrrolidin-3- yloxy]-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 8.96 (s, 2H), 7.86 (s, 1H), 7.54-7.52(m, 1H), 7.52- 7.51 (m, 1H), 7.45-7.42 (m, 1H), 6.89 (d, J = 6.4 Hz,1H), 5.37 (m, 1H), 5.06-4.94 (m, 1H), 3.30-3.20 (m, 2H), 3.18- 2.99 (m,2H), 2.61-2.50 (m, 3H), 2.23-2.12 (m, 1H), 2.10-2.02 (m, 1H), 1.72 (d, J= 7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 2.03 min, MS (ESIpos):m/z = 478.1 (M + H)⁺. 204

3-{[3- fluoropiperidin- 4-yl]oxy}-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide, as amixture of cis isomers ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s,2H), 7.86 (d, J = 1.5 Hz, 1H), 7.61-7.57 (m, 1H), 7.53 (d, J = 1.2 Hz,1H), 7.45 (s, 1H), 6.64 (d, J = 5.8 Hz, 1H), 5.35 (q, J = 7.1 Hz, 1H),4.66-4.49 (m, 2H), 3.44-3.33 (m, 1H), 3.05 (d, J = 13.2 Hz, 1H), 2.88(dd, J = 13.0, 7.4 Hz, 1H), 2.74 (dd, J = 12.6, 9.3 Hz, 1H), 2.54 (d, J= 1.0 Hz, 3H), 2.17 (d, J = 10.7 Hz, 1H), 1.71 (t, J = 7.3 Hz, 4H). LCMS(Analytical Method D) Rt = 3.28 min, MS (ESIpos): m/z = 510 (M + H)⁺.

Example 205 (Diastereoisomer 1) and Example 206 (Diastereoisomer 2)3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,formed as a Mixture of 2 Diastereoisomers

To a solution of Example 190 (189 mg, 0.32 mmol) in DCM (1 mL) was addedTFA (0.25 mL, 3.19 mmol) and the resulting mixture stirred at RT for 16h. The mixture was concentrated at reduced pressure and the residuetaken up in water (1 mL) and basified to pH 12 with 10 M NaOH solutionto give a white precipitate. The precipitate was dissolved and extractedwith EtOAc (2×5 mL). The combined organics were dried over MgSO₄,filtered and concentrated at reduced pressure to give 160 mg(quantitative yield) of the title compound as white powder.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.17 (d, J=7.1 Hz, 1H), 9.11 (s, 2H),7.91 (s, 1H), 7.64 (d, J=1.2 Hz, 1H), 7.59-7.55 (m, 1H), 7.54-7.50 (m,1H), 5.29 (m, 1H), 4.48 (dt, J=7.5, 3.9 Hz, 1H), 3.15 (d, J=12.2 Hz,1H), 2.82 (dt, J=11.8, 4.4 Hz, 1H), 2.62 (dt, J=30.0, 8.9 Hz, 2H), 2.02(s, 1H), 1.77-1.67 (m, 1H), 1.61 (d, J=7.1 Hz, 3H), 1.49 (ddt, J=13.1,9.3, 5.1 Hz, 1H).

Example 205: Diastereoisomer 1;3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

HPLC Chiral Purification (Method 4) was performed on 60 mg ofDiastereoisomer 1 (Example 205) and Diastereoisomer 2 (Example 206)mixture to give 24.6 mg of the title compound.

HPLC Chiral Analysis (Method 4): 100% e.e. Rt=10.2 min.

¹H NMR (500 MHz, DMSO): δ [ppm] 9.18 (d, 1H), 9.12 (s, 2H), 7.91 (t,1H), 7.64 (d, 1H), 7.58-7.55 (m, 1H), 7.55-7.51 (m, 1H), 5.30 (m, 1H),4.48 (tt, 1H), 3.18-3.11 (m, 1H), 2.85-2.77 (m, 1H), 2.67-2.54 (m, 2H),2.06-1.99 (m, 1H), 1.75-1.69 (m, 1H), 1.64-1.44 (m, 5H).

LCMS (Analytical Method F) Rt=2.08 min, MS (ESIpos): m/z=492 (MH)⁺.

Example 206: Diastereoisomer 2;3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

HPLC Chiral Purification (Method 4) was performed on 60 mg ofDiastereoisomer 1 (Example 205) and Diastereoisomer 2 (Example 206)mixture to give 24.6 mg of the title compound.

HPLC Chiral Analysis (Method 4): 96% e.e. Rt=12.4 min.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.17 (d, J=7.1 Hz, 1H), 9.11 (s, 2H),7.90 (s, 1H), 7.64 (d, J=1.1 Hz, 1H), 7.57-7.54 (m, 2H), 7.54-7.50 (m,1H), 5.29 (m, 1H), 4.42 (dt, J=8.2, 4.2 Hz, 1H), 3.16-3.07 (m, 1H),2.85-2.74 (m, 1H), 2.60-2.52 (m, 2H), 2.08-2.00 (m, 1H), 1.74-1.65 (m,1H), 1.64-1.41 (m, 5H).

LCMS (Analytical Method F) Rt=2.08 min, MS (ESIpos): m/z=492 (MH)⁺.

Intermediate 67 was formed as a mixture of two cis isomers. SFC ChiralPurification (Method 5) provided Example 207 (Cis Isomer 1) and Example208 (Cis Isomer 2).

Example 207 Cis Isomer 1;3-(5-methyl-1,3-thiazol-2-yl)-5-{[2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral Purification (Method 5) on 46.9 mg of Intermediate 67 gave15.3 mg of the title compound.

SFC Chiral Analysis (Method 2): 99.6% e.e., Rt=1.66 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.96 (s, 2H), 7.88 (s, 1H),7.59-7.53 (m, 2H), 7.45-7.41 (m, 1H), 6.63 (d, J=6.5 Hz, 1H), 5.38 (m,1H), 4.47 (ddd, J=15.5, 11.0, 4.4 Hz, 1H), 3.36-3.23 (m, 2H), 2.80 (td,J=12.6, 2.4 Hz, 1H), 2.57 (d, J=1.0 Hz, 3H), 2.41-2.33 (m, 1H),2.27-2.18 (m, 1H), 1.75 (d, J=7.2 Hz, 3H), 1.68-1.60 (m, 3H).

LCMS (Analytical Method D) Rt=3.69 min, MS (ESIpos): m/z=560 (M+H)⁺.

Example 208 Cis Isomer 2;3-(5-methyl-1,3-thiazol-2-yl)-5-{[2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral Purification (Method 5) on 46.9 mg of Intermediate 67 gave 14.1mg of the title compound.

SFC Chiral Analysis (Method 5): 99.6% e.e., Rt=1.87 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.85 (s, 1H),7.55-7.51 (m, 2H), 7.44-7.38 (m, 1H), 6.61 (d, J=6.4 Hz, 1H), 5.35 (m,1H), 4.48-4.38 (m, 1H), 3.32-3.19 (m, 2H), 2.78 (td, J=12.6, 2.3 Hz,1H), 2.54 (d, J=0.9 Hz, 3H), 2.35-2.29 (m, 1H), 2.23-2.15 (m, 1H), 1.72(d, J=7.2 Hz, 3H), 1.67-1.59 (m, 3H)

LCMS (Analytical Method D) Rt=3.70 min, MS (ESIpos): m/z=560 (M+H)⁺.

Example 2093-{[2-methyl-2-azabicyclo[2.2.1]hept-5-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 74 (30 mg, 0.06 mmol), formaldehyde (37% in water) (22.32μL, 0.3 mmol) and acetic acid (5.12 μL, 0.09 mmol) were combined in MeOH(2 mL) and STAB (37.88 mg, 0.18 mmol) was added. The resulting solutionwas stirred at RT for 1 hour before concentrating under reducedpressure. The resulting residue was taken up in saturated NaHCO₃ (5 mL)and extracted with DCM (3×5 mL). The combined organics were washed withwater and dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified by preparative HPLC (Method A)and freeze-dried from MeCN/water to give 13.7 mg (44% yield) of thetitle compound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.82 (t, J=1.3 Hz,1H), 7.52 (d, J=1.2 Hz, 1H), 7.49-7.47 (m, 1H), 7.37-7.35 (m, 1H), 6.60(d, J=6.0 Hz, 1H), 5.36 (m, 1H), 4.38 (d, J=6.1 Hz, 1H), 3.21 (s, 1H),2.84 (m, 1H), 2.60 (d, J=3.4 Hz, 1H), 2.53 (d, J=1.1 Hz, 3H), 2.43-2.37(m, 1H), 2.33 (s, 3H), 2.15-2.09 (m, 1H), 1.77 (d, J=10.0 Hz, 1H), 1.71(d, J=7.2 Hz, 3H), 1.48 (d, J=13.8 Hz, 1H).

LCMS (Analytical Method F) Rt=2.21 min, MS (ESIpos): m/z=518.1 (M+H)⁺.

In analogy to the procedure described for Example 220/Example 221, thefollowing examples were prepared using STAB and the appropriate aminestarting materials.

Ex. Structure Name Analytical Data 210

3-[(1- methylpiperidin- 4-yl)oxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl} benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 7.86 (t, J = 1.4 Hz, 1H), 7.82 (d, J =8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.59-7.56 (m, 1H), 7.52 (d, J =1.2 Hz, 1H), 7.45 (d, J = 7.1 Hz, 1H), 7.42-7.39 (m, 1 H), 5.60 (m, 1H), 4.53-4.45 (m, 1H), 2.76-2.63 (m, 2H), 2.53 (d, J = 1.1 Hz, 3H),2.40-2.27 (m, 5H), 2.10-2.00 (m, 2H), 1.94-1.84 (m, 2H), 1.76 (d, J =7.0 Hz, 3H). LCMS (Analytical Method F) Rt = 2.06 min, MS (ESIpos): m/z= 506.3 (M + H)⁺. 211

3-[(1- methylazetidin- 3-yl)oxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl} benzamide ¹H NMR(250 MHz, Chloroform-d): δ [ppm] 7.88 (s, 3H), 7.82 (d, J = 8.7 Hz, 1H),7.74 (d, J = 8.7 Hz, 1H), 7.62-7.36 (m, 3H), 7.27 (d, J = 1.6 Hz, 1H),5.59 (m, 1H), 4.84 (p, J = 5.6 Hz, 1H), 3.84 (dt, J = 6.0, 2.4 Hz, 2H),3.14 (dt, J = 7.2, 3.3 Hz, 2H), 2.51 (d, J = 1.0 Hz, 3H), 2.40 (s, 3H),1.74 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method F) Rt = 1.90 min, MS(ESIpos): m/z = 478 (M + H)⁺. 212

3-[(3-fluoro-1- methylpiperidin-4- yl)oxy]-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide, as a single unknown isomer ¹H NMR (500 MHz, Chloroform-d): δ[ppm] 8.94 (s, 2H), 7.88-7.83 (m, 1H), 7.58 (dt, J = 2.6, 1.4 Hz, 1H),7.52 (d, J = 1.2 Hz, 1H), 7.46- 7.42 (m, 1H), 6.63 (d, J = 6.3 Hz, 1H),5.35 (m, 1H), 4.71 (dtd, J = 49.1, 8.0, 4.4 Hz, 1H), 4.44 (tt, J = 11.3,5.8 Hz, 1H), 3.04 (t, J = 12.4 Hz, 1H), 2.70 (d, J = 11.5 Hz, 1H), 2.54(d, J = 1.1 Hz, 3H), 2.35 (s, 4H), 2.28-2.15 (m, 2H), 1.80 (tdd, J =13.6, 10.0, 3.8 Hz, 1H), 1.72 (d, J = 7.1 Hz, 3H). LCMS (AnalyticalMethod F) Rt = 2.12 min, MS (ESIpos): m/z = 524.2 (M + H)⁺. 213

3-{[1- (dimethylamino) cyclopropyl] methoxy}- 5-(5-methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.82 (s,1H), 7.56-7.50 (m, 2H), 7.39-7.34 (m, 1H), 6.63 (d, J = 6.2 Hz, 1H),5.37 (m, 1H), 4.07 (s, 2H), 2.57- 2.52 (m, 3H), 2.51 (s, 6H), 1.72 (d, J= 7.1 Hz, 3H), 0.81 (s, 2H), 0.75-0.68 (m, 2H). LCMS (Analytical MethodD) Rt = 3.46 min, MS (ESIpos): m/z = 506.0 (M + H)⁺. 214

3-[(2-methyl-2- azaspiro [3.3]hept- 6-yl)oxy]-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.89 (s, 2H), 7.81 (t,1H), 7.45 (d, 1H), 7.34 (dd, 1H), 7.25- 7.20 (m, 1H), 7.08 (d, 1H), 5.31(m, 1H), 4.60 (p, 1H), 3.25-3.20 (m, 2H), 3.20-3.15 (m, 2H), 2.72- 2.62(m, 2H), 2.48 (d, 3H), 2.27- 2.20 (m, 5H), 1.64 (d, 3H). LCMS(Analytical Method D) Rt = 3.21 min, MS (ESIpos): m/z 518 (M + H)⁺. 215

N-{[(1R)-1-[2- (difluoromethyl) pyrimidin-5- yl]ethyl}-3-[(1-methylpiperidin- 4-yl)oxy]-5-(5- methyl-1,3- thiazol-2- yl)benzamide ¹HNMR (500 MHz, Chloroform-d): δ [ppm] 8.89 (s, 2H), 7.80 (s, 1H),7.53-7.48 (m, 2H), 7.40-7.36 (m, 1H), 6.78-6.52 (m, 2H), 5.34 (m, 1H),4.47-4.42 (m, 1H), 2.73- 2.64 (m, 2H), 2.52 (d, J = 1.0 Hz, 3H),2.35-2.25 (m, 5H), 2.06- 1.98 (m, 2H), 1.90-1.79 (m, 2H), 1.69 (d, J =7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 1.85 min, MS (ESIpos): m/z= 488.2 (M + H)⁺. 216

3-{[(3-endo)-8- methyl-8- azabicyclo[3.2.1] oct-3-yl]oxy}-5-(5-methyl-1,3- thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl)pyrimidin-5- yl]ethyl} benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm]8.94 (s, 2H), 7.78 (t, J = 1.3 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.43(dd, J = 2.2, 1.5 Hz, 1H), 7.34-7.29 (m, 1H), 6.73 (d, J = 6.5 Hz, 1H),5.36 (m, 1H), 4.64 (t, J = 4.9 Hz, 1H), 3.17 (s, 2H), 2.53 (d, J = 1.1Hz, 3H), 2.32 (s, 3H), 2.25-2.18 (m, 2H), 2.10- 2.01 (m, 4H), 1.95 (d, J= 14.6 Hz, 2H), 1.72 (d, J = 7.2 Hz, 3H). LCMS (Analytical Method D) Rt= 3.43 min, MS (ESIpos) m/z = 532.1 (M + H)⁺. 217

3-{[(3-exo)-8- methyl-8- azabicyclo[3.2.1] oct-3-yl]oxy}- 5-(5-methyl-1,3- thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl} benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.92 (s,2H), 7.81 (t, J = 1.3 Hz, 1H), 7.50 (d, J = 1.2 Hz, 1H), 7.47 (dd, J =2.3, 1.5 Hz, 1H), 7.39-7.34 (m, 1H), 6.75 (d, J = 6.5 Hz, 1H), 5.34 (m,1H), 4.60 (ddd, J = 16.6, 10.6, 6.1 Hz, 1H), 3.28-3.24 (m, 2H), 2.52 (d,J = 1.1 Hz, 3H), 2.36 (s, 3H), 2.11- 2.04 (m, 2H), 2.02-1.96 (m, 2H),1.84 (t, J = 11.9 Hz, 2H), 1.70 (d, J = 7.2 Hz, 3H), 1.68-1.63 (m, 2H).LCMS (Analytical Method D) Rt = 3.36 min, MS (ESIpos) m/z = 532.1 (M +H)⁺. 218

3-{[(4aS,7R, 7aR)-4- methyloctahydro- cyclopenta [b][1,4] oxazin-7-yl]oxy}-5- (5-methyl-1,3- thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl)pyrimidin-5- yl]ethyl} benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm]8.93 (s, 2H), 7.90-7.78 (m, 1H), 7.56 (s, 1H), 7.52-7.49 (m, 1H), 7.40(s, 1H), 6.70 (s, 1H), 5.34 (m, 1H), 4.80-4.56 (m, 1H), 3.98 (d, J =11.7 Hz, 1H), 3.90- 3.76 (m, 1H), 3.73-3.57 (m, 1H), 2.84-2.67 (m, 1H),2.52 (s, 3H), 2.42-2.35 (m, 1H), 2.31 (s, 3H), 2.24 (s, 1H), 1.97 (s,2H), 1.82- 1.73 (m, 1H), 1.70 (d, J = 7.1 Hz, 3H), 1.70-1.55 (m, 1H).LCMS (Analytical Method F) Rt = 2.19 min, MS (ESIpos): m/z = 548.2 (M +H)⁺. 219

3-{[(4aS,7S, 7aR)-4- methylocta- hydro- cyclopenta[b] [1,4]oxazin-7-yl]oxy}-5- (5-methyl-1,3- thiazol-2-yl)-N- {(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide ¹H NMR (500 MHz,DMSO-d6): δ [ppm] 9.16 (d, J = 7.1 Hz, 1H), 9.11 (s, 2H), 7.88 (s, 1H),7.66- 7.63 (m, 1H), 7.53 (s, 1H), 7.52- 7.49 (m, 1H), 5.29 (m, 1H), 4.92(s, 1H), 3.93-3.74 (m, 1H), 3.67- 3.54 (m, 1H), 3.28 (m, 1H), 2.71- 2.58(m, 1H), 2.33-1.84 (m, 7H), 1.68 (dt, J = 15.5, 8.6 Hz, 1H), 1.60 (d, J= 7.1 Hz, 3H), 1.41- 1.17 (m, 1H), thiazole CH₃ peak obscured bysolvent. LCMS (Analytical Method F) Rt = 2.18 min, MS (ESIpos): m/z =548.1 (M + H)⁺.

Example 220 (Diastereoisomer 1) and Example 221 (Diastereoisomer 2)3-[(1-methylpiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,Formed as a mixture of 2 diastereoisomers

Intermediate 40 (93 mg, 0.189 mmol), 37% formaldehyde solution in water(0.07 mL, 0.946 mmol) and acetic acid (0.02 mL, 0.378 mmol) werecombined in methanol (1 mL) and STAB (60 mg, 0.28 mmol) was addedportionwise. The resulting solution was stirred at RT for 2 h beforeconcentrating at reduced pressure. The residue was taken up in water (1mL) and basified to pH 5 with 10 M sodium hydroxide solution andextracted with EtOAc. The organic phase was separated, dried (MgSO₄),filtered, evaporated at reduced pressure and freeze dried to give 59 mg(62% yield) of the title compound as white solid.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.17 (d, J=7.1 Hz, 1H), 9.11 (s, 2H),7.91 (s, 1H), 7.64 (d, J=1.2 Hz, 1H), 7.59-7.55 (m, 1H), 7.54-7.50 (m,1H), 5.29 (m, 1H), 4.48 (dt, J=7.5, 3.9 Hz, 1H), 3.15 (d, J=12.2 Hz,1H), 2.82 (dt, J=11.8, 4.4 Hz, 1H), 2.62 (dt, J=30.0, 8.9 Hz, 2H), 2.02(s, 1H), 1.77-1.67 (m, 1H), 1.61 (d, J=7.1 Hz, 3H), 1.49 (ddt, J=13.1,9.3, 5.1 Hz, 1H).

Example 220: Diastereoisomer 1;3-[(1-methylpiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral Purification (Method 6) on 56 mg of Diastereoisomer 1(Example 220) and Diastereoisomer 2 (Example 221) mixture gave 29 mg ofthe title compound.

SFC Chiral Analysis (Method 6): 99.8% e.e., Rt=2.01 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.86 (t, J=1.4 Hz,1H), 7.57 (dd, J=2.3, 1.5 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 7.45-7.40 (m,1H), 6.80 (d, J=6.6 Hz, 1H), 5.35 (m, 1H), 4.54 (dt, J=7.2, 3.7 Hz, 1H),2.78 (d, J=10.4 Hz, 1H), 2.52 (d, J=1.1 Hz, 4H), 2.39 (s, 1H), 2.29 (s,4H), 1.95-1.83 (m, 2H), 1.70 (d, J=7.2 Hz, 3H), 1.63 (dd, J=10.6, 5.5Hz, 2H).

LCMS (Analytical Method D) Rt=3.16 min, MS (ESIpos): m/z=506 (M+H)+.

Example 221: Diastereoisomer 2;3-[(1-methylpiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral Purification (Method 6) on 56 mg of Diastereoisomer 1(Example 220) and

Diastereoisomer 2 (Example 221) mixture gave 20.1 mg of the titlecompound.

SFC Chiral Analysis (Method 6): 95.1% e.e., Rt=2.19 min.

¹H NMR (250 MHz, MeOD): δ [ppm] 9.01 (s, 2H), 7.91 (t, 1H), 7.67-7.59(m, 1H), 7.54 (d, 1H), 7.51-7.45 (m, 1H), 5.34 (q, 1H), 4.64-4.53 (m,1H), 2.90 (d, 1H), 2.67-2.29 (m, 9H), 2.06-1.82 (m, 2H), 1.75-1.57 (m,5H).

LCMS (Analytical Method D) Rt=3.15 min, MS (ESIpos): m/z=506 (M+H)+.

Example 222 (Cis Isomer 1) and Example 223 (Cis Isomer 2)3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-methyl-2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,Formed as a Mixture of Cis-Isomers

Intermediate 67 (50 mg, 0.09 mmol), 37% formaldehyde solution in water(33 μL, 0.45 mmol) and acetic acid (5 μL) were combined in methanol (3mL) and STAB (57 mg, 0.27 mmol) was added and the reaction was stirredfor 2 h. LCMS showed incomplete conversion. The reaction mixture wasre-treated with 37% formaldehyde solution in water (33 μL, 0.45 mmol)and STAB (57 mg, 0.27 mmol) and stirred for a further 1 h. The reactionrequired five further re-treatments to drive to completion. The crudereaction mixture was concentrated under reduced pressure, the resultingresidue taken up in saturated NaHCO₃ (2 mL) solution and extracted withDCM (3×2 mL). The combined organic phase was dried (MgSO₄), filtered,concentrated at reduced pressure and freeze-dried from MeCN/water togive 46.6 mg (86% yield) of the title compound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.85 (d, J=1.3 Hz,1H), 7.55-7.49 (m, 2H), 7.39 (s, 1H), 6.61 (d, J=4.7 Hz, 1H), 5.35 (m,1H), 4.39 (dq, J=9.9, 4.8, 4.2 Hz, 1H), 3.03 (dt, J=12.2, 3.5 Hz, 1H),2.80-2.71 (m, 1H), 2.56-2.50 (m, 3H), 2.45 (s, 3H), 2.41 (d, J=12.6 Hz,1H), 2.36-2.28 (m, 1H), 2.17-2.08 (m, 1H), 1.88-1.74 (m, 2H), 1.72 (d,J=7.2 Hz, 3H).

LCMS (Analytical Method F) Rt=3.31 min, MS (ESIpos): m/z=574.1 (M+H)⁺.

Example 222: Cis Isomer 1;3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-methyl-2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral Purification (Method 7) on 43.9 mg of Cis Isomer 1 (Example222) and Cis Isomer 2 (Example 223) mixture gave 11.7 mg of the titlecompound.

SFC Chiral Analysis (Method 7): 98.2% e.e., Rt=1.51 min

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.96 (s, 2H), 7.88 (s, 1H),7.58-7.52 (m, 2H), 7.46-7.37 (m, 1H), 6.63 (d, J=6.3 Hz, 1H), 5.38 (m,1H), 4.49-4.35 (m, 1H), 3.09-3.02 (m, 1H), 2.78 (s, 1H), 2.56 (d, J=0.9Hz, 3H), 2.47 (s, 3H), 2.46-2.40 (m, 1H), 2.35 (d, J=11.0 Hz, 1H), 2.14(d, J=12.3 Hz, 1H), 1.89-1.76 (m, 2H), 1.75 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method D) Rt=4.26 min, MS (ESIpos): m/z=574 (M+H)⁺.

Example 223: Cis Isomer 2;3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-methyl-2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral purification (Method 7) on 43.9 mg of Cis Isomer 1 (Example222) and Cis

Isomer 2 (Example 223) mixture gave 9.5 mg of the title compound.

SFC Chiral Analysis (Method 7): 98.6% e.e., Rt=1.76 min

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.85 (s, 1H),7.55-7.51 (m, 2H), 7.39 (s, 1H), 6.61 (d, J=6.4 Hz, 1H), 5.35 (m, 1H),4.40 (dt, J=10.5, 5.9 Hz, 1H), 3.06-3.00 (m, 1H), 2.82-2.68 (m, 1H),2.54 (s, 3H), 2.45 (s, 3H), 2.41 (d, J=11.7 Hz, 1H), 2.31 (d, J=12.5 Hz,1H), 2.13 (d, J=13.4 Hz, 1H), 1.80 (p, J=12.4 Hz, 2H), 1.72 (d, J=7.2Hz, 3H).

LCMS (Analytical Method D) Rt=4.27 min, MS (ESIpos): m/z=574 (M+H)⁺.

Example 2243-(5-Methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)piperidin-4-yl]oxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

Example 201 (50 mg, 0.1 mmol) in DCE (1 mL), acetone (1 mL) and aceticacid (50 μL) was stirred at RT for 30 min. STAB (65 mg, 0.3 mmol) wasadded and the reaction stirred overnight. The reaction mixture wasre-treated with acetone (1 mL) and STAB (65 mg, 0.3 mmol) and stirredovernight. The reaction was again re-treated with acetone (3 mL) andSTAB (130 mg, 0.6 mmol) and stirred for 4 h. The reaction mixture wasconcentrated under reduced pressure and the residue taken up insaturated NaHCO₃ (5 mL) and extracted with DCM (3×5 mL). The combinedorganics were dried over MgSO₄, filtered and concentrated under reducedpressure. The compound was freeze-dried from acetonitrile/water to give48.0 mg (88% yield) of the title compound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.87-7.84 (m, 1H), 7.82 (d,J=8.7, 1H), 7.74 (d, J=8.7, 1H), 7.57 (dd, J=2.3, 1.5, 1H), 7.53-7.51(m, 1H), 7.44 (d, J=7.2, 1H), 7.41 (dd, J=2.3, 1.6, 1H), 5.64-5.55 (m,1H), 4.51-4.42 (m, 1H), 2.84-2.72 (m, 3H), 2.53 (d, J=1.1, 3H),2.50-2.38 (m, 2H), 2.11-1.99 (m, 2H), 1.91-1.80 (m, 2H), 1.76 (d, J=7.0,3H), 1.07 (d, J=6.5, 6H).

LCMS (Analytical Method D) Rt=3.22 min, MS (ESIpos): m/z=534.2 (M+H)⁺.

In analogy to the procedure described for Example 224, the followingexample was prepared using STAB and the appropriate ketone and aminestarting materials.

Ex. Structure Name Analytical Data 225

3-(5-methyl- 1,3-thiazol- 2-yl)-5- {[(3S)-1- (propan-2- yl)pyrrolidin-3-yl]oxy}-N- {(1R)-1- [2-(trifluoro- methyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.85 (s,1H), 7.57-7.46 (m, 2H), 7.40 (s, 1H), 6.77 (s, 1H), 5.36 (m, 1H), 5.03-4.90 (m, 1H), 3.08-2.91 (m, 3H), 2.69-2.56 (m, 1H), 2.56-2.45 (m, 4H),2.45-2.28 (m, 1H), 2.13- 1.98 (m, 1H), 1.71 (d, J = 7.1 Hz, 3H), 1.17(d, J = 3.6 Hz, 3H), 1.14 (d, J = 3.6 Hz, 3H). LCMS (Analytical MethodD) Rt = 3.35 min, MS (ESIpos): m/z = 520 (M + H)⁺.

Example 226 Methyl4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate

To a solution of Example 138 (60 mg, 0.12 mmol) and DIPEA (0.11 mL, 0.61mmol) in DCM (1 mL) was added methyl carbonochloridate (0.028 mL, 0.37mmol) and the resulting solution stirred at RT for 3 h. The solution wasdiluted with DCM (5 mL) and washed with water (2 mL). The organic phasewas dried (MgSO₄), filtered and concentrated at reduced pressure and thecrude material purified by Biotage Isolera™ chromatography (onpre-packed KP-SiO₂ column, eluting with heptane-EtOAc). The purifiedmaterial was freeze-dried from MeCN/water to give 53 mg (79% yield) ofthe title compound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.82 (s, 1H),7.55-7.49 (m, 2H), 7.39 (s, 1H), 6.75 (d, J=6.6 Hz, 1H), 5.36 (m, 1H),4.62 (tt, J=6.9, 3.4 Hz, 1H), 3.76-3.68 (m, 5H), 3.45-3.38 (m, 2H), 2.53(s, 3H), 1.99-1.90 (m, 2H), 1.81-1.73 (m, 2H), 1.71 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method D) Rt=4.53, MS (ESIpos) m/z=550 (M+H)⁺.

Example 227 Ethyl4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate

To a solution of Example 138 (60 mg, 0.12 mmol) and DIPEA (0.11 mL, 0.61mmol) in DCM (1 mL) was added ethyl carbonochloridate (0.035 mL, 0.37mmol) and the resulting solution stirred at RT for 3 h. The solution wasdiluted with DCM (5 mL) and washed with water (2 mL). The organic phasewas dried (MgSO₄), filtered and concentrated at reduced pressure and thecrude material purified by Biotage Isolera™ chromatography (onpre-packed KP-SiO₂ column, eluting with heptane-EtOAc). The purifiedmaterial was freeze-dried from MeCN/water to give 53 mg (79% yield) ofthe title compound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.82 (t, J=1.3 Hz,1H), 7.53 (dd, J=2.3, 1.5 Hz, 1H), 7.52 d, J=1.1 Hz, 1H), 7.42-7.37 (m,1H), 6.74 (d, J=6.6 Hz, 1H), 5.36 (m, 1H), 4.66-4.58 (m, 1H), 4.14 (q,J=7.1 Hz, 2H), 3.77-3.68 (m, 2H), 3.45-3.36 (m, 2H), 2.53 (d, J=1.0 Hz,3H), 1.99-1.90 (m, 2H), 1.81-1.73 (m, 2H), 1.71 (d, J=7.2 Hz, 3H), 1.27(t, J=7.1 Hz, 3H).

LCMS (Analytical Method D) Rt=4.70, MS (ESIpos) m/z=564 (M+H)⁺.

Example 228 Ethyl(3S)-3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]pyrrolidine-1-carboxylate

To a solution of Example 203 (40 mg, 0.08 mmol) and DIPEA (73 μL, 0.42mmol) in DCM (1 mL) was added ethyl carbonochloridate (24 μL, 0.25 mmol)and the resulting solution stirred at RT for 3 h. The solution wasdiluted with DCM (5 mL) and washed with water (2 mL). The organic phasewas dried (MgSO₄), filtered and concentrated at reduced pressure and thecrude material purified by Biotage Isolera™ chromatography (onpre-packed KP-SiO₂ column, eluting with heptane-EtOAc, 3:2 to 0:1). Thepurified material was freeze-dried from MeCN/water to give 32.5 mg (71%yield) of the title compound as white powder.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.95 (s, 2H), 7.91 (s, 1H), 7.54(s, 1H), 7.52-7.48 (m, 1H), 7.37 (s, 1H), 6.75 (d, J=6.8 Hz, 1H),5.44-5.25 (m, 1H), 5.03 (m, 1H), 4.23-4.07 (m, 2H), 3.65 (s, 4H), 2.54(s, 3H), 2.21 (m, 2H), 1.73 (d, J=7.1 Hz, 3H), 1.26 (m, 3H).

LCMS (Analytical Method D) Rt=4.52 min, MS (ESIpos): m/z=550.15 (M+H)⁺.

Example 2293-(5-Methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)azetidin-3-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A solution of Intermediate 35 (20 mg, 0.043 mmol), 2-bromopropane (6.1μL, 0.065 mmol) and potassium carbonate (11.9 mg, 0.086 mmol) inacetonitrile (0.5 mL) was heated in the microwave at 60° C. for 10 minsthen at 100° C. for 30 mins. The reaction was re-treated with excess2-bromopropane (˜50 μL) and heated at 100° C. for 2 h. The reactionmixture was filtered and concentrated under reduced pressure. The crudematerial was purified by prep-TLC, eluting with 1% NH3 in 5% MeOH inDCM. The material was then freeze-dried from MeCN/water to give 12.9 mg(59% yield) of the title compound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.95 (s, 2H), 7.88 (s, 1H), 7.52(d, J=1.1 Hz, 1H), 7.46-7.40 (m, 1H), 7.31 (s, 1H), 6.81 (s, 1H), 5.37(m, 1H), 5.02-4.89 (m, 1H), 3.99 (s, 2H), 3.29 (s, 2H), 2.58 (s, 1H),2.53 (d, J=1.0 Hz, 3H), 1.72 (d, J=7.2 Hz, 3H), 1.05 (d, J=6.2 Hz, 6H).

LCMS (Analytical Method D) Rt=3.34 min, MS (ESIpos): m/z=506.1 (M+H)⁺.

Intermediate 93 was formed as a mixture of cis-isomers. SFC ChiralPurification (Method 10) provided Example 230 (Cis Isomer 1) and Example231 (Cis Isomer 2).

Example 230 Cis Isomer 1;3-[(−3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

SFC Chiral Purification (Method 10) on 243 mg of Intermediate 93 gave45.8 mg of the title compound as a white powder.

SFC Chiral Analysis (Method 10): 100% e.e., Rt=1.59 min

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.27 (d, J=7.0, 1H), 8.24 (d, J=8.8,1H), 8.03 (d, J=8.8, 1H), 7.96-7.89 (m, 1H), 7.64 (d, J=1.2, 1H),7.59-7.52 (m, 2H), 5.54-5.41 (m, 1H), 4.85 (d, J=4.7, 1H), 4.50-4.36 (m,1H), 3.84-3.71 (m, 1H), 2.54-2.51 (m, 3H), 1.65 (d, J=7.2, 3H), 1.21 (d,J=6.2, 3H), 1.12 (d, J=6.4, 3H).

LCMS (Analytical Method F) Rt=3.11 min, MS (ESIpos): m/z=481.1 (M+H)+.

Example 231 Cis Isomer 2;3-[(−3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

SFC Chiral Purification (Method 10) on 243 mg of Intermediate 93 gave43.8 mg of the title compound as a white powder.

SFC Chiral Analysis (Method 10): 100% e.e., Rt=2.51 min

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.27 (d, J=7.0, 1H), 8.24 (d, J=8.8,1H), 8.03 (d, J=8.8, 1H), 7.95-7.90 (m, 1H), 7.64 (d, J=1.2, 1H),7.59-7.52 (m, 2H), 5.52-5.45 (m, 1H), 4.84 (d, J=4.8, 1H), 4.47-4.39 (m,1H), 3.83-3.75 (m, 1H), 2.54-2.51 (m, 3H), 1.65 (d, J=7.2, 3H), 1.22 (d,J=6.2, 3H), 1.11 (d, J=6.4, 3H).

LCMS (Analytical Method F) Rt=3.10 min, MS (ESIpos): m/z=481.1 (M+H)+.

Example 2323-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A mixture of Intermediate 5AZ (158 mg, 430 μmol), Intermediate VI (103mg, 451 μmol), HATU (229 mg, 602 μmol) and DIPEA (300 μl, 1.7 mmol) inDMF (3.0 mL) was stirred at RT until complete conversion. The reactionmixture was evaporated to dryness under reduced pressure and theremaining material purified by preparative HPLC (method 1) to give 90 mg(39% yield) of the title compound.

LCMS (method 1): rt: 1.14 min, MS ES+ m/z=541 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.62 (d, 3 H) 2.25 (d, 4 H) 3.08-3.32(m, 4 H) 4.93 (br. s., 1 H) 5.30 (t, 1 H) 7.55-7.61 (m, 1 H) 7.63-7.74(m, 2 H) 7.95 (s, 1 H) 9.05-9.25 (m, 3 H).

In analogy to the procedure described for the preparation of Example 232the following derivatives have been prepared:

Ex. Structure Name Analytical Data 233

3-[(1,1- dioxidotetrahydro- 2H-thiopyran-4- yl)oxy]-5-(5- methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[6- (trifluoromethyl) pyridin-3-yl]ethyl}benzamide ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, 3 H), 2.24 (m, 4 H)3.10-3.31 (m, 4 H) 4.92 (t, 1 H) 5.30 (t, 1 H) 7.53-7.74 (m, 3 H) 7.95(t, 1 H) 9.05-9.24 (m, 3 H). LCMS (method 1): Rt = 1.16 min, MS ES+ m/z= 540 (M + H)⁺. 234

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5- (tetrahydro-2H- pyran-4- yloxy)benzamide LCMS (method 1):rt: 1.18 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H), 1.54 (d, 3 H) 1.58-1.70 (m, 2 H) 1.91-2.08 (m, 2 H)2.47 (s, 3 H) 2.90 (dd, 2 H) 3.52 (m, 2 H) 3.85 (m, 2 H) 4.67-4.81 (m, 1H) 5.12-5.31 (m, 1 H) 7.52-7.61 (m, 2 H) 7.67 (t, 1 H) 7.94 (t, 1 H)8.44- 8.59 (m, 2 H) 9.02-9.14 (m, 1 H). 235

3-(5-ethyl-1,3- thiazol-2-yl)-N-[(6- methylpyridazin-3- yl)methyl]-5-(tetrahydro-2H- pyran-4- yloxy)benzamide ¹H NMR (400 MHz, METHANOL- d₄)δ [ppm] 1.38 (t, 3 H) 1.72- 1.87 (m, 2 H) 2.06-2.21 (m, 2 H) 2.69 (s, 3H) 2.96 (dd, 2 H) 3.65 (s, 2 H) 3.94-4.06 (m, 2 H) 4.66-4.81 (m, 1 H)4.87 (s, 2 H) 7.55 (dd, 1 H) 7.59-7.65 (m, 2 H) 7.66-7.76 (m, 2 H) 7.97(t, 1 H). 236

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5- (tetrahydro-2H- pyran-4- yloxy)benzamide LCMS (method 1):rt: 1.31 min, MS ES+ m/z = 479 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.54 (d, 3 H) 1.64 (m, 2 H) 1.85-1.94 (m, 1 H) 1.95- 2.05 (m, 3 H)2.08-2.20 (m, 2 H) 2.43 (m, 2 H) 2.47 (s, 3 H) 3.44-3.59 (m, 2 H)3.76-3.91 (m, 3 H) 4.76 (s, 1 H) 5.23 (s, 1 H) 7.48-7.63 (m, 2 H) 7.68(d, 1 H) 7.95 (t, 1 H) 8.45-8.60 (m, 2 H) 9.09 (d, 1 H). 237

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(6- methylpyridazin-3-yl)methyl]-5- (tetrahydro-2H- pyran-4- yloxy)benzamide ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.64 (s, 2 H) 1.82-1.94 (m, 1 H) 2.00 (m, 3 H) 2.13 (m,2 H) 2.43 (m, 2 H) 2.60 (s, 3 H) 3.43-3.60 (m, 2 H) 3.74-3.93 (m, 3 H)4.73 (m, 3 H) 7.48- 7.64 (m, 4 H) 7.68 (d, 1 H) 7.98 (t, 1 H) 9.38 (s, 1H). 238

3-(5-cyclobutyl- 1,3-thiazol-2-yl)-5- (tetrahydro-2H- pyran-4-yloxy)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide LCMS(method 1): rt: 1.42 min, MS ES+ m/z = 533 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.52-1.71 (m, 5 H) 1.81- 1.94 (m, 1 H) 1.95-2.06 (m, 3H) 2.08-2.21 (m, 2 H) 2.35- 2.47 (m, 2 H) 3.52 (m, 2 H) 3.72- 3.95 (m, 3H) 4.69-4.84 (m, 1 H) 5.29 (s, 1 H) 7.53 (dd, 1 H) 7.57-7.63 (m, 1 H)7.68 (d, 1 H) 7.94 (t, 1 H) 9.06-9.20 (m, 3 H). 239

3-(5-cyclobutyl- 1,3-thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3-ylmethoxy]-N- {(1S)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS (method 2): rt: 1.42 min, MS ES+ m/z = 533 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61 (d, 3 H) 1.66-1.78 (m, 1 H)1.81-1.95 (m, 1 H) 1.95- 2.08 (m, 2 H) 2.09-2.23 (m, 2 H) 2.43 (dt, 2 H)2.62-2.75 (m, 1 H) 3.51-3.71 (m, 2 H) 3.73- 3.90 (m, 3 H) 3.95-4.17 (m,2 H) 5.30 (s, 1 H) 7.50-7.61 (m, 2 H) 7.68 (d, 1 H) 7.95 (t, 1 H)9.07-9.20 (m, 3 H). 240

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(3R)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.04 min, MS ES+ m/z = 439 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.59 (d, 3 H) 1.93-2.09 (m, 1 H) 2.18-2.31 (m, 1 H)2.59 (s, 3 H) 2.90 (dd, 2 H) 3.71-4.00 (m, 4 H) 5.21 (d, 1 H) 5.37 (m, 1H) 7.46- 7.56 (m, 3 H) 7.56-7.63 (m, 1 H) 7.68 (t, 1 H) 7.97 (t1 H) 9.14(d, 1 H). 241

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(3R)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.14 min, MS ES+ m/z = 439 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.54 (d, 3 H) 1.95-2.05 (m, 1 H) 2.16-2.32 (m, 1 H)2.47 (s, 3 H) 2.85-2.99 (m, 2 H) 3.72-3.97 (m, 4 H) 5.14-5.29 (m, 2 H)7.44-7.57 (m, 1 H) 7.68 (t, 1 H) 7.96 (t, 1 H) 8.49 (d, 1 H) 8.56 (d, 1H) 9.10 (d, 1 H). 242

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3-yloxy]-N-{(1R)-1- [2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamideLCMS (method 1): rt: 1.28 min, MS ES+ m/z = 493 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.29 (t, 3 H) 1.61 (d, 3 H) 1.93-2.07 (m, 1 H)2.26 (m, 1 H) 2.83-2.98 (m, 2 H) 3.72- 3.97 (m, 4 H) 5.21 (d, 1 H) 5.30(t, 1 H) 7.52 (m, 2 H) 7.68 (s, 1 H) 7.94 (t, 1 H) 9.07-9.22 (m, 3 H).243

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(3R)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.17 min, MS ES+ m/z = 465 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.59 (d, 3 H) 1.79-2.07 (m, 3 H) 2.09-2.31 (m, 3 H) 2.36-2.48 (m,2 H) 2.59 (s, 3 H) 3.69-3.98 (m, 5 H) 5.21 (d, 1 H) 5.37 (t, 1 H)7.46-7.64 (m, 4 H) 7.69 (d, 1 H) 7.98 (t, 1 H) 9.14 (d, 1 H) 244

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(3R)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.26 min, MS ES+ m/z = 465 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.55 (d, 3 H) 1.84-2.07 (m, 3 H) 2.08-2.31 (m, 3 H) 2.39-2.46 (m,2 H) 2.47 (s, 3 H) 3.72-3.98 (m, 5 H) 5.13-5.30 (m, 2 H) 7.53 (dt, 2 H)7.68 (d, 1 H) 7.97 (t, 1 H) 8.49 (d, 1 H) 8.56 (d, 1 H) 9.08 (d, 1 H).245

3-(5-cyclobutyl- 1,3-thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3-yloxy]-N-{(1R)-1- [2-(trifluoromethyl) pyrimidin-5-yl] ethyl}benzamideLCMS (method 1): rt: 1.39 min, MS ES+ m/z = 519 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.61 (d, 3 H) 1.81-2.07 (m, 3 H) 2.08-2.35 (m, 3H) 2.44 (dt, 2 H) 3.72-3.98 (m, 5 H) 5.21 (d, 1 H) 5.30 (t, 1 H)7.45-7.59 (m, 2 H) 7.69 (d, 1 H) 7.95 (t, 1 H) 9.05-9.21 (m, 3 H). 246

N-[(1R)-1-(6- methylpyridazin-3- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(3R)- tetrahydrofuran-3- yloxy]benzamide LCMS (method1): rt: 1.12 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.33 (d, 6 H) 1.59 (d, 3 H) 1.90-2.07 (m, 1 H) 2.25 (s, 1 H) 2.59(s, 3 H) 3.28 (d, 1 H) 3.70- 3.99 (m, 4 H) 5.21 (d, 1 H) 5.37 (t, 1 H)7.48-7.64 (m, 4 H) 7.69 (d, 1 H) 7.97 (s, 1 H) 9.13 (d, 1 H). 247

N-[(1R)-1-(5- methylpyrazin-2- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(3R)- tetrahydrofuran-3- yloxy]benzamide LCMS (method1): rt: 1.21 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.33 (d, 6 H) 1.55 (d, 3 H) 1.95-2.06 (m, 1 H) 2.26 (m, 1 H) 2.47(s, 3 H) 3.28 (m, 1 H) 3.71-4.00 (m, 4 H) 5.15-5.32 (m, 2 H) 7.53 (m, 2H) 7.69 (d, 1 H) 7.96 (t, 1 H) 8.49 (s, 1 H) 8.56 (d, 1 H) 9.08 (d, 1H). 248

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(3R)- tetrahydrofuran-3-yloxy]-N-{(1R)-1- [2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamideLCMS (method 1): rt: 1.34 min, MS ES+ m/z = 507 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) d [ppm] 1.33 (d, 6 H) 1.61 (d, 3 H) 1.93-2.07 (m, 1 H)2.25 (m, 1 H) 3.28 (m, 1 H) 3.67-4.01 (m, 4 H) 5.21 (d, 1 H) 5.30 (t, 1H) 7.45-7.59 (m, 2 H) 7.69 (d, 1 H) 7.95 (t, 1 H) 9.06-9.20 (m, 3 H).249

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(3S)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.04 min, MS ES+ m/z = 439 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.59 (d, 3 H) 1.95-2.07 (m, 1 H) 2.18-2.31 (m, 1 H)2.59 (s, 3 H) 2.81-2.98 (m, 2 H) 3.71-3.97 (m, 4 H) 5.21 (d, 1 H) 5.37(t, 1 H) 7.49- 7.63 (m, 4 H) 7.68 (t, 1 H) 7.97 (t, 1 H) 9.14 (d, 1 H).250

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(3S)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.13 min, MS ES+ m/z = 439 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.54 (d, 3 H) 2.02 (m, 1 H) 2.19-2.31 (m, 1 H) 2.47(s, 3 H) 2.82-2.99 (m, 2 H) 3.70-4.00 (m, 4 H) 5.13- 5.31 (m, 2 H) 7.53(m, 2 H) 7.68 (s, 1 H) 7.96 (t, 1 H) 8.45-8.61 (m, 2 H) 9.08 (d, 1 H).251

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3-yloxy]-N-{(1R)-1- [2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamideLCMS (method 1): rt: 1.28 min, MS ES+ m/z = 493 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.29 (t, 3 H) 1.61 (d, 3 H) 1.89-2.09 (m, 1 H)2.25 (m, 1 H) 2.90 (q, 2 H) 3.69-3.99 (m, 4 H) 5.21 (d, 1 H) 5.30 (t, 1H) 7.43-7.58 (m, 2 H) 7.68 (s, 1 H) 7.89-8.00 (m, 1 H) 9.06-9.20 (m, 3H). 252

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(3S)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.17 min, MS ES+ m/z = 465 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) d[ppm] 1.59 (d, 3 H) 1.84-2.08 (m, 3 H) 2.09-2.34 (m, 3 H) 2.44 (m, 2 H)2.59 (s, 3 H) 3.74- 3.95 (m, 5 H) 5.21 (d, 1 H) 5.37 (m, 1 H) 7.50-7.63(m, 4 H) 7.68 (d, 1 H) 7.98 (t, 1 H) 9.13 (d, 1 H). 253

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(3S)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.26 min, MS ES+ m/z = 465 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.55 (d, 3 H) 1.83-2.07 (m, 3 H) 2.08-2.31 (m, 3 H) 2.39-2.46 (m,2 H) 2.47 (s, 3 H) 3.73-3.97 (m, 5 H) 5.13-5.31 (m, 2 H) 7.45-7.58 (m, 2H) 7.68 (d, 1 H) 7.97 (t, 1 H) 8.43- 8.62 (m, 2 H) 9.08 (d, 1 H). 254

3-(5-cyclobutyl- 1,3-thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3-yloxy]-N-{(1R)-1- [2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamideLCMS (method 1): rt: 1.39 min, MS ES+ m/z = 519 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.61 (d, 3 H) 1.79-2.06 (m, 3 H) 2.08-2.36 (m, 3H) 2.36-2.47 (m, 2 H) 3.66-3.98 (m, 5 H) 5.21 (d, 1 H) 5.30 (t, 1 H)7.44-7.59 (m, 2 H) 7.69 (d, 1 H) 7.95 (t, 1 H) 9.08-9.22 (m, 3 H). 255

N-[(1R)-1-(6- methylpyridazin-3- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(3S)- tetrahydrofuran-3- yloxy]benzamide LCMS (method1): rt: 1.12 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.33 (d, 6 H) 1.59 (d, 3 H) 1.92-2.09 (m, 1 H) 2.17-2.31 (m, 1 H)2.59 (s, 3 H) 3.28 (m, 1 H) 3.70-3.98 (m, 4 H) 5.13- 5.26 (m, 1 H) 5.37(m, 1 H) 7.48- 7.63 (m, 4 H) 7.69 (d, 1 H) 7.97 (t, 1 H) 9.14 (d, 1 H).256

N-[(1R)-1-(5- methylpyrazin-2- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(3S)- tetrahydrofuran-3- yloxy]benzamide LCMS (method1): rt: 1.21 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.33 (d, 6 H) 1.54 (d, 3 H) 1.92-2.09 (m, 1 H) 2.17-2.32 (m, 1 H)2.47 (s, 3 H) 3.28 (m, 1 H) 3.70-3.99 (m, 4 H) 5.15- 5.31 (m, 2 H)7.44-7.58 (m, 2 H) 7.69 (d, 1 H) 7.96 (t, 1 H) 8.43-8.60 (m, 2 H) 9.09(d, 1 H). 257

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(3S)- tetrahydrofuran-3-yloxy]-N-{(1R)-1- [2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamideLCMS (method 1): rt: 1.34 min, MS ES+ m/z = 507 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.61 (d, 3 H) 1.93-2.08 (m, 1 H)2.26 (m, 1 H) 3.28 (m, 1 H) 3.71-3.97 (m, 4 H) 5.16-5.24 (m, 1 H) 5.30(t, 1 H) 7.43-7.61 (m, 2 H) 7.69 (d, 1 H) 7.95 (t, 1 H) 9.07-9.24 (m, 3H). 258

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(3R)- tetrahydrofuran-3- ylmethoxy] benzamide LCMS (method1): rt: 1.10 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.59 (d, 3 H) 1.64-1.79 (m, 1 H) 1.95-2.13 (m, 1 H)2.59 (s, 3 H) 2.63-2.76 (m, 1 H) 2.85-2.98 (m, 2 H) 3.58 (dd, 1 H) 3.68(m, 1 H) 3.73-3.87 (m, 2 H) 4.05 (m, 2 H) 5.37 (t, 1 H) 7.46- 7.63 (m, 4H) 7.67 (s, 1 H) 7.96 (s, 1 H) 9.12 (d, 1 H). 259

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(3R)- tetrahydrofuran-3- ylmethoxy] benzamide LCMS (method1): rt: 1.18 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.55 (d, 3 H) 1.72 (m, 1 H) 1.95-2.11 (m, 1 H) 2.47(s, 3 H) 2.60-2.77 (m, 1 H) 2.81-2.97 (m, 2 H) 3.58 (dd, 1 H) 3.62-3.71(m, 1 H) 3.73-3.89 (m, 2 H) 3.94-4.16 (m, 2 H) 5.23 (t, 1 H) 7.51-7.60(m, 2 H) 7.67 (s, 1 H) 7.95 (t, 1 H) 8.43-8.60 (m, 2 H) 9.07 (d, 1 H).260

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3- ylmethoxy]-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide LCMS(method 1): rt: 1.32 min, MS ES+ m/z = 507 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.29 (t, 3 H) 1.61 (d, 3 H) 1.65-1.78 (m, 1 H)1.95-2.13 (m, 1 H) 2.60-2.77 (m, 1 H) 2.90 (dd, 2 H) 3.57 (dd, 1 H) 3.67(d, 1 H) 3.74-3.88 (m, 2 H) 4.05 (dd, 2 H) 5.30 (m, 1 H) 7.55 (dt, 2 H)7.67 (s, 1 H) 7.94 (t, 1 H) 9.07-9.21 (m, 3 H). 261

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(3R)- tetrahydrofuran-3- ylmethoxy] benzamide LCMS (method1): rt: 1.22 min, MS ES+ m/z = 479 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.59 (d, 3 H) 1.64-1.76 (m, 1 H) 1.82-1.95 (m, 1 H) 1.95-2.22 (m,4 H) 2.35-2.48 (m, 2 H) 2.59 (s, 3 H) 2.63-2.74 (m, 1 H) 3.58 (dd, 1 H)3.67 (d, 1 H) 3.74-3.90 (m, 3 H) 3.96- 4.16 (m, 2 H) 5.37 (m, 1 H) 7.45-7.62 (m, 4 H) 7.68 (d, 1 H) 7.97 (t, 1 H) 9.12 (d, 1 H). 262

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(3R)- tetrahydrofuran-3- ylmethoxy] benzamide LCMS (method1): rt: 1.31 min, MS ES+ m/z = 479 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.55 (d, 3 H) 1.65-1.76 (m, 1 H) 1.84-2.21 (m, 5 H) 2.43 (m, 2 H)2.47 (s, 3 H) 2.62-2.73 (m, 1 H) 3.58 (dd, 1 H) 3.67 (d, 1 H) 3.73-3.90(m, 3 H) 3.95-4.14 (m, 2 H) 5.16-5.30 (m, 1 H) 7.52-7.61 (m, 2 H) 7.67(d, 1 H) 7.96 (t, 1 H) 8.44-8.61 (m, 2 H) 9.07 (d, 1 H). 263

3-(5-cyclobutyl- 1,3-thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3-ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide LCMS (method 1): rt: 1.43 min, MS ES+ m/z = 533 (M + H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, 3 H) 1.66-1.77 (m, 1 H)1.84-2.21 (m, 5 H) 2.43 (m, 2 H) 2.61-2.75 (m, 1 H) 3.57 (dd, 1 H) 3.67(d, 1 H) 3.73-3.89 (m, 3 H) 3.96-4.13 (m, 2 H) 5.30 (m, 1 H) 7.55 (dt, 2H) 7.68 (s, 1 H) 7.95 (s, 1 H) 9.06-9.21 (m, 3 H). 264

N-[(1R)-1-(6- methylpyridazin-3- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(3R)- tetrahydrofuran-3- ylmethoxy] benzamide LCMS(method 1): rt: 1.17 min, MS ES+ m/z = 467 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.59 (d, 3 H) 1.64-1.78 (m, 1 H)1.97-2.11 (m, 1 H) 2.59 (s, 3 H) 2.63-2.75 (m, 1 H) 3.27 (m, 1 H) 3.58(dd, 1 H) 3.67 (d, 1 H) 3.74-3.88 (m, 2 H) 3.96-4.14 (m, 2 H) 5.37 (t, 1H) 7.45-7.64 (m, 4 H) 7.68 (d, 1 H) 7.97 (t, 1 H) 9.12 (d, 1 H). 265

N-[(1R)-1-(5- methylpyrazin-2- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(3R)- tetrahydrofuran-3- ylmethoxy] benzamide LCMS(method 1): rt: 1.26 min, MS ES+ m/z = 467 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.55 (d, 3 H) 1.63-1.79 (m, 1 H)1.94-2.12 (m, 1 H) 2.47 (s, 3 H) 2.59-2.79 (m, 1 H) 3.28 (m, 1 H) 3.58(dd, 1 H) 3.67 (d, 1 H) 3.73-3.88 (m, 2 H) 4.05 (m, 2 H) 5.24 (m, 1 H)7.55 (dt, 2 H) 7.68 (d, 1 H) 7.96 (t, 1 H) 8.42-8.60 (m, 2 H) 9.07 (d, 1H). 266

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(3R)- tetrahydrofuran-3-ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS (method 1): rt: 1.38 min, MS ES+ m/z = 521 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.61 (d, 3 H) 1.71(m, 1 H) 1.96-2.12 (m, 1 H) 2.68 (m, 1 H) 3.24-3.30 (m, 1 H) 3.57 (dd, 1H) 3.61-3.71 (m, 1 H) 3.72-3.86 (m, 2 H) 3.96-4.15 (m, 2 H) 5.30 (t, 1H) 7.55 (dt, 2 H) 7.68 (d, 1 H) 7.94 (t, 1 H) 9.07-9.21 (m, 3 H). 267

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(2R)- tetrahydrofuran-2- ylmethoxy] benzamide LCMS (method1): rt: 1.11 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.59 (d, 3 H) 1.67-1.78 (m, 1 H) 1.79-1.95 (m, 2 H)1.96-2.10 (m, 1 H) 2.59 (s, 3 H) 2.90 (m, 2 H) 3.63- 3.73 (m, 1 H)3.75-3.86 (m, 1 H) 3.97-4.13 (m, 2 H) 4.15- 4.27 (m, 1 H) 5.37 (t, 1 H)7.47- 7.62 (m, 4 H) 7.67 (t, 1 H) 7.96 (t, 1 H) 9.14 (d, 1 H). 268

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(2R)- tetrahydrofuran-2- ylmethoxy] benzamide LCMS (method1): rt: 1.20 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.54 (d, 3 H) 1.67-1.77 (m, 1 H) 1.78-1.95 (m, 2 H)1.96-2.07 (m, 1 H) 2.47 (s, 3 H) 2.90 (m, 2 H) 3.60- 3.74 (m, 1 H)3.75-3.85 (m, 1 H) 3.98-4.14 (m, 2 H) 4.14- 4.28 (m, 1 H) 5.23 (m, 1 H)7.55 (d, 2 H) 7.67 (t, 1 H) 7.95 (t, 1 H) 8.43-8.61 (m, 2 H) 9.09 (d, 1H). 269

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(2R)- tetrahydrofuran-2- ylmethoxy]-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide LCMS(method 1): rt: 1.34 min, MS ES+ m/z = 507 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.29 (t, 3 H) 1.61 (d, 3 H) 1.75 (m, 1 H) 1.85 (m, 2 H)1.96- 2.08 (m, 1 H) 2.90 (m, 2 H) 3.62-3.74 (m, 1 H) 3.75-3.85 (m, 1 H)4.00-4.14 (m, 2 H) 4.14-4.25 (m, 1 H) 5.30 (t, 1 H) 7.48-7.60 (m, 2 H)7.68 (t, 1 H) 7.93 (t, 1 H) 9.07-9.20 (m, 3 H). 270

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(2R)- tetrahydrofuran-2- ylmethoxy] benzamide LCMS (method1): rt: 1.24 min, MS ES+ m/z = 479 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.59 (d, 3 H) 1.75 (m, 1 H) 1.80-1.94 (m, 3 H) 1.96- 2.07 (m, 2 H)2.08-2.23 (m, 2 H) 2.37-2.47 (m, 2 H) 2.59 (s, 3 H) 3.64-3.74 (m, 1 H)3.75- 3.87 (m, 2 H) 3.98-4.14 (m, 2 H) 4.15-4.26 (m, 1 H) 5.37 (t, 1 H)7.45-7.63 (m, 4 H) 7.68 (d, 1 H) 7.97 (t, 1 H) 9.13 (d, 1 H). 271

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(2R)- tetrahydrofuran-2- ylmethoxy] benzamide LCMS (method1): rt: 1.32 min, MS ES+ m/z = 479 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.55 (d, 3 H) 1.75 (m, 1 H) 1.79-1.94 (m, 3 H) 1.96- 2.07 (m, 2 H)2.08-2.22 (m, 2 H) 2.38-2.46 (m, 2 H) 2.46- 2.48 (s, 3 H) 3.64-3.75 (m,1 H) 3.76-3.88 (m, 2 H) 4.01-4.13 (m, 2 H) 4.14-4.26 (m, 1 H) 5.23 (t, 1H) 7.51-7.60 (m, 2 H) 7.68 (d, 1 H) 7.96 (t, 1 H) 8.46- 8.58 (m, 2 H)9.08 (d, 1 H). 272

3-(5-cyclobutyl- 1,3-thiazol-2-yl)-5- [(2R)- tetrahydrofuran-2-ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide LCMS (method 1): rt: 1.44 min, MS ES+ m/z = 533 (M + H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, 3 H) 1.67-1.78 (m, 1 H)1.79-2.07 (m, 5 H) 2.08-2.21 (m, 2 H) 2.37-2.46 (m, 2 H) 3.64-3.74 (m, 1H) 3.76-3.89 (m, 2 H) 4.02-4.13 (m, 2 H) 4.14-4.25 (m, 1 H) 5.30 (m, 1H) 7.50-7.59 (m, 2 H) 7.68 (d, 1 H) 7.95 (t, 1 H) 9.08-9.19 (m, 3 H).273

N-[(1R)-1-(6- methylpyridazin-3- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(2R)- tetrahydrofuran-2- ylmethoxy] benzamide LCMS(method 1): rt: 1.19 min, MS ES+ m/z = 467 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.30-1.37 (m, 6 H) 1.59 (d, 3 H) 1.66-2.10 (m, 4 H)2.59 (s, 3 H) 3.28 (m, 1 H) 3.69 (m, 1 H) 3.79 (m, 1 H) 4.00- 4.14 (m, 2H) 4.15-4.26 (m, 1 H) 5.37 (m, 1 H) 7.48-7.63 (m, 4 H) 7.68 (d, 1 H)7.96 (t, 1 H) 9.13 (d, 1 H). 274

N-[(1R)-1-(5- methylpyrazin-2- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(2R)- tetrahydrofuran-2- ylmethoxy] benzamide LCMS(method 1): rt: 1.27 min, MS ES+ m/z = 467 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.30-1.38 (m, 6 H) 1.55 (d, 3 H) 1.67-1.77 (m, 1 H)1.80-1.95 (m, 2 H) 1.96-2.08 (m, 1 H) 2.47 (s, 3 H) 3.28 (m, 1 H)3.63-3.74 (m, 1 H) 3.75- 3.85 (m, 1 H) 4.02-4.13 (m, 2 H) 4.15-4.26 (m,1 H) 5.23 (m, 1 H) 7.52-7.60 (m, 2 H) 7.68 (d, 1 H) 7.96 (t, 1 H) 8.49(d, 1 H) 8.56 (d, 1 H) 9.08 (d, 1 H). 275

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(2R)- tetrahydrofuran-2-ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide LCMS (method 1): rt: 1.40 min, MS ES+ m/z = 521 (M + H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.61 (d, 3 H) 1.68-1.78 (m,1 H) 1.79-1.95 (m, 2 H) 1.96-2.07 (m, 1 H) 3.28 (m, 1 H) 3.65-3.73 (m, 1H) 3.76-3.84 (m, 1 H) 4.01- 4.13 (m, 2 H) 4.19 (m, 1 H) 5.30 (m, 1 H)7.50-7.60 (m, 2 H) 7.69 (d, 1 H) 7.94 (t, 1 H) 9.08- 9.19 (m, 3 H). 276

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(3S)- tetrahydrofuran-3- ylmethoxy] benzamide LCMS (method1): rt: 1.10 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.59 (d, 3 H) 1.64-1.81 (m, 1 H) 1.96-2.12 (m, 1 H)2.59 (s, 3 H) 2.63-2.77 (m, 1 H) 2.84-2.98 (m, 2 H) 3.58 (dd, 1 H) 3.67(m, 1 H) 3.74-3.88 (m, 2 H) 3.96-4.14 (m, 2 H) 5.37 (m, 1 H) 7.49- 7.63(m, 4 H) 7.67 (t, 1 H) 7.96 (t, 1 H) 9.12 (d, 1 H). 277

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(3S)- tetrahydrofuran-3- ylmethoxy] benzamide LCMS (method1): rt: 1.18 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.55 (d, 3 H) 1.72 (m, 1 H) 1.99-2.12 (m, 1 H) 2.47(s, 3 H) 2.60-2.77 (m, 1 H) 2.90 (m, 2 H) 3.58 (dd, 1 H) 3.62-3.72 (m, 1H) 3.74-3.89 (m, 2 H) 3.95-4.14 (m, 2 H) 5.23 (m, 1 H) 7.49-7.61 (m, 2H) 7.67 (t, 1 H) 7.95 (t, 1 H) 8.48 (d, 1 H) 8.56 (d, 1 H) 9.07 (d, 1H). 278

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3- ylmethoxy]-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide LCMS(method 1): rt: 1.32 min, MS ES+ m/z = 507 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.29 (t, 3 H) 1.61 (d, 3 H) 1.65-1.81 (m, 1 H)1.95-2.13 (m, 1 H) 2.60-2.77 (m, 1 H) 2.90 (m, 2 H) 3.58 (dd, 1 H) 3.67(m, 1 H) 3.72-3.88 (m, 2 H) 4.05 (m, 2 H) 5.30 (m, 1 H) 7.46-7.60 (m, 2H) 7.67 (t, 1 H) 7.94 (t, 1 H) 9.06-9.21 (m, 3 H). 279

N-[(1R)-1-(6- methylpyridazin-3- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(3S)- tetrahydrofuran-3- ylmethoxy] benzamide LCMS(method 1): rt: 1.17 min, MS ES+ m/z = 467 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.59 (d, 3 H) 1.64-1.79 (m, 1 H)1.94-2.12 (m, 1 H) 2.59 (s, 3 H) 2.63-2.75 (m, 1 H) 3.28 (m, 1 H) 3.58(dd, 1 H) 3.67 (m, 1 H) 3.73-3.90 (m, 2 H) 4.02 (m, 2 H) 5.37 (m, 1 H)7.45-7.62 (m, 4 H) 7.68 (d, 1 H) 7.97 (t, 1 H) 9.12 (d, 1 H). 280

N-[(1R)-1-(5- methylpyrazin-2- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(3S)- tetrahydrofuran-3- ylmethoxy] benzamide LCMS(method 1): rt: 1.26 min, MS ES+ m/z = 467 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.55 (d, 3 H) 1.64-1.82 (m, 1 H)1.95-2.12 (m, 1 H) 2.47 (s, 3 H) 2.60-2.76 (m, 1 H) 3.28 (m, 1 H) 3.58(dd, 1 H) 3.67 (m, 1 H) 3.81 (m, 2 H) 4.05 (m, 2 H) 5.24 (m, 1 H) 7.49-7.61 (m, 2 H) 7.68 (d, 1 H) 7.96 (t, 1 H) 8.49 (d, 1 H) 8.56 (d, 1 H)9.07 (d, 1 H). 281

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(3S)- tetrahydrofuran-3-ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS (method 1): rt: 1.38 min, MS ES+ m/z = 521 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) d [ppm] 1.33 (d, 6 H) 1.61 (d, 3 H)1.66-1.78 (m, 1 H) 1.98-2.11 (m, 1 H) 2.61-2.76 (m, 1 H) 3.27 (m, 1 H)3.57 (dd, 1 H) 3.67 (m, 1 H) 3.73-3.86 (m, 2 H) 4.05 (m, 2 H) 5.30 (m, 1H) 7.53 (dd, 1 H) 7.57 (dd, 1 H) 7.68 (d, 1 H) 7.94 (t, 1 H) 9.07- 9.18(m, 3 H). 282

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(2S)- tetrahydrofuran-2- ylmethoxy] benzamide LCMS (method1): rt: 1.11 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.59 (d, 3 H) 1.66-1.78 (m, 1 H) 1.79-1.95 (m, 2 H)1.96-2.11 (m, 1 H) 2.59 (s, 3 H) 2.90 (m, 2 H) 3.61- 3.73 (m, 1 H)3.75-3.85 (m, 1 H) 3.98-4.14 (m, 2 H) 4.15- 4.28 (m, 1 H) 5.37 (m, 1 H)7.44- 7.63 (m, 4 H) 7.67 (t, 1 H) 7.96 (t, 1 H) 9.14 (d, 1 H). 283

3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(2S)- tetrahydrofuran-2- ylmethoxy] benzamide LCMS (method1): rt: 1.20 min, MS ES+ m/z = 453 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.29 (t, 3 H) 1.54 (d, 3 H) 1.65-1.78 (m, 1 H) 1.80-1.94 (m, 2 H)1.97-2.09 (m, 1 H) 2.47 (s, 3 H) 2.90 (m, 2 H) 3.70 (m, 1 H) 3.79 (m, 1H) 3.99- 4.14 (m, 2 H) 4.15-4.26 (m, 1 H) 5.23 (m, 1 H) 7.55 (d, 2 H)7.67 (t, 1 H) 7.95 (t, 1 H) 8.49 (d, 1 H) 8.56 (d, 1 H) 9.09 (d, 1 H).284

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(2S)- tetrahydrofuran-2- ylmethoxy]-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide LCMS(method 1): rt: 1.34 min, MS ES+ m/z = 507 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.29 (t, 3 H) 1.61 (d, 3 H) 1.66-1.77 (m, 1 H)1.78-1.95 (m, 2 H) 1.96-2.09 (m, 1 H) 2.90 (m, 2 H) 3.64-3.73 (m, 1 H)3.79 (m, 1 H) 3.99-4.14 (m, 2 H) 4.15-4.25 (m, 1 H) 5.30 (m, 1 H)7.49-7.60 (m, 2 H) 7.68 (t, 1 H) 7.93 (t, 1 H) 9.07- 9.22 (m, 3 H). 285

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(2S)- tetrahydrofuran-2- ylmethoxy] benzamide LCMS (method1): rt: 1.24 min, MS ES+ m/z = 479 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.59 (d, 3 H) 1.66-1.78 (m, 1 H) 1.90 (m, 3 H) 1.96- 2.07 (m, 2 H)2.08-2.21 (m, 2 H) 2.36-2.48 (m, 2 H) 2.59 (s, 3 H) 3.69 (m, 1 H) 3.80(m, 2 H) 3.99-4.14 (m, 2 H) 4.15-4.25 (m, 1 H) 5.37 (m, 1 H) 7.49- 7.63(m, 4 H) 7.68 (d, 1 H) 7.97 (t, 1 H) 9.14 (d, 1 H). 286

3-(5-cyclobutyl- 1,3-thiazol-2-yl)- N-[(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(2S)- tetrahydrofuran-2- ylmethoxy]benzamide LCMS (method1): rt: 1.32 min, MS ES+ m/z = 479 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) d[ppm] 1.54 (d, 3 H) 1.67-1.78 (m, 1 H) 1.90 (m, 3 H) 1.96- 2.07 (m, 2 H)2.08-2.21 (m, 2 H) 2.43 (m, 2 H) 2.47 (s, 3 H) 3.69 (m, 1 H) 3.76-3.88(m, 2 H) 3.97-4.14 (m, 2 H) 4.14- 4.27 (m, 1 H) 5.23 (m, 1 H) 7.51- 7.60(m, 2 H) 7.68 (d, 1 H) 7.96 (t, 1 H) 8.49 (d, 1 H) 8.56 (d, 1 H) 9.10(d, J = 7.35 Hz, 1 H). 287

3-(5-cyclobutyl- 1,3-thiazol-2-yl)-5- [(2S)- tetrahydrofuran-2-ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS (method 1): rt: 1.44 min, MS ES+ m/z = 533 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, 3 H) 1.66-1.78 (m, 1 H)1.80-1.94 (m, 3 H) 2.00 (m, 2 H) 2.14 (m, 2 H) 2.43 (m, 2 H) 3.70 (m, 1H) 3.74- 3.91 (m, 2 H) 3.98-4.13 (m, 2 H) 4.14-4.27 (m, 1 H) 5.19- 5.37(m, 1 H) 7.44-7.61 (m, 2 H) 7.68 (d, 1 H) 7.95 (t, 1 H) 9.05-9.23 (m, 3H). 288

N-[(1R)-1-(6- methylpyridazin-3- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(2S)- tetrahydrofuran-2- ylmethoxy] benzamide LCMS(method 1): rt: 1.19 min, MS ES+ m/z = 467 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.59 (d, 3 H) 1.66-1.77 (m, 1 H)1.79-1.95 (m, 2 H) 1.96-2.09 (m, 1 H) 2.59 (s, 3 H) 3.21-3.31 (m, 1 H)3.70 (m, 1 H) 3.79 (m, 1 H) 4.08 (m, 2 H) 4.15-4.26 (m, 1 H) 5.37 (m, 1H) 7.46-7.63 (m, 4 H) 7.69 (d, 1 H) 7.97 (t, 1 H) 9.14 (d, 1 H). 289

N-[(1R)-1-(5- methylpyrazin-2- yl)ethyl]-3-[5- (propan-2-yl)-1,3-thiazol-2-yl]-5- [(2S)- tetrahydrofuran-2- ylmethoxy]benzamide LCMS(method 1): rt: 1.28 min, MS ES+ m/z = 467 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.54 (d, 3 H) 1.65-1.77 (m, 1 H)1.79-1.95 (m, 2 H) 1.96-2.10 (m, 1 H) 2.47 (s, 3 H) 3.28 (m, 1 H) 3.70(m, 1 H) 3.79 (m, 1 H) 3.98- 4.14 (m, 2 H) 4.15-4.26 (m, 1 H) 5.23 (m, 1H) 7.49-7.61 (m, 2 H) 7.68 (d, 1 H) 7.96 (t, 1 H) 8.49 (d, 1 H) 8.56 (d,1 H) 9.09 (d, 1 H). 290

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(2S)- tetrahydrofuran-2-ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS (method 1): rt: 1.40 min, MS ES+ m/z = 521 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.61 (d, 3 H)1.66-1.77 (m, 1 H) 1.78-1.94 (m, 2 H) 1.96-2.10 (m, 1 H) 3.28 (m, 1 H)3.64-3.74 (m, 1 H) 3.75-3.86 (m, 1 H) 3.98- 4.14 (m, 2 H) 4.15-4.27 (m,1 H) 5.30 (m, 1 H) 7.49-7.61 (m, 2 H) 7.69 (d, 1 H) 7.94 (t, 1 H)9.04-9.22 (m, 3 H). 291

3-(5-methyl-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3-yloxy]-N-{(1S)-1- [2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamideLCMS (method 1): rt: 1.20 min, MS ES+ m/z = 479 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) d [ppm] 1.60 (d, 3 H) 1.93-2.09 (m, 1 H) 2.18-2.31 (m, 1H) 3.72-3.97 (m, 4 H) 5.13-5.37 (m, 2 H) 7.46-7.58 (m, 2 H) 7.65 (d, 1H) 7.93 (t, 1 H) 9.05- 9.25 (m, 3 H). 292

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3- ylmethoxy]-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl] ethyl}benzamide LCMS(method 1): rt: 1.29 min, MS ES+ m/z = 507 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.29 (t, 3 H) 1.57-1.78 (m, 4 H) 1.95-2.13 (m, 1 H)2.61-2.79 (m, 1 H) 2.90 (m, 2 H) 3.58 (dd, 1 H) 3.63-3.72 (m, 1 H)3.73-3.88 (m, 2 H) 3.94- 4.19 (m, 2 H) 5.49 (m, 1 H) 7.57 (m, 2 H) 7.68(t, 1 H) 7.92-8.11 (m, 2 H) 8.25 (d, 1 H) 9.29 (d, 1 H). 293

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(3R)- tetrahydrofuran-3-ylmethoxy]-N- {(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl]ethyl}benzamide LCMS (method 1): rt: 1.35 min, MS ES+ = 521 (M + H)⁺.¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.65 (m, 4 H) 1.95-2.15(m, 1 H) 2.62- 2.78 (m, 1 H) 3.28 (m, 1 H) 3.51- 3.61 (m, 1 H) 3.67 (m,1 H) 3.73-3.89 (m, 2 H) 3.95-4.17 (m, 2 H) 5.49 (m, 1 H) 7.50- 7.64 (m,2 H) 7.69 (d, 1 H) 7.91- 8.10 (m, 2 H) 8.25 (d, 1 H) 9.29 (d, 1 H). 294

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(3R)- tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamideLCMS (method 1): rt: 1.31 min, MS ES+ m/z = 507 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.65 (d, 3 H) 1.93-2.10 (m, 1 H)2.18-2.31 (m, 1 H) 3.28 (m, 1 H) 3.67- 4.01 (m, 4 H) 5.13-5.28 (m, 1 H)5.49 (m, 1 H) 7.48-7.62 (m, 2 H) 7.70 (d, 1 H) 7.94-8.10 (m, 2 H) 8.25(d, 1 H) 9.29 (d, 1 H). 295

3-(5-cyclobutyl- 1,3-thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamideLCMS (method 1): rt: 1.35 min, MS ES+ m/z = 519 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.65 (d, 3 H) 1.82-2.06 (m, 3 H) 2.07-2.31 (m, 3H) 2.43 (m, 2 H) 3.70-3.99 (m, 5 H) 5.22 (m, 1 H) 5.49 (m, 1 H)7.47-7.60 (m, 2 H) 7.69 (d, 1 H) 7.94-8.14 (m, 2 H) 8.25 (d, 1 H) 9.29(d, 1 H). 296

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3- ylmethoxy]-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamide LCMS(method 1): rt: 1.29 min, MS ES+ m/z = 507 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.29 (t, 3 H) 1.65 (m, 4 H) 1.91-2.12 (m, 1 H) 2.61-2.78 (m, 1 H) 2.90 (m, 2 H) 3.58 (dd, 1 H) 3.67 (m, 1 H) 3.73- 3.88 (m,2 H) 3.94-4.17 (m, 2 H) 5.49 (m, 1 H) 7.57 (m, 2 H) 7.68 (t, 1 H)7.92-8.10 (m, 2 H) 8.25 (d, 1 H) 9.29 (d, 1 H). 297

3-(5-cyclobutyl- 1,3-thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3-ylmethoxy]-N- {(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl]ethyl}benzamide LCMS (method 1): rt: 1.39 min, MS ES+ m/z = 533 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.65 (m, 4 H) 1.83-1.95 (m, 1 H)1.96-2.09 (m, 2 H) 2.10- 2.23 (m, 2 H) 2.35-2.48 (m, 2 H) 2.61-2.78 (m,1 H) 3.58 (dd, 1 H) 3.67 (m, 1 H) 3.73-3.89 (m, 3 H) 3.94-4.15 (m, 2 H)5.49 (m, 1 H) 7.52-7.62 (m, 2 H) 7.68 (d, 1 H) 7.93-8.09 (m, 2 H) 8.25(d, 1 H) 9.29 (d, 1 H). 298

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(3S)- tetrahydrofuran-3-ylmethoxy]-N- {(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl]ethyl}benzamide LCMS (method 1): rt: 1.35 min, MS ES+ m/z = 521 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.65 (m, 4 H)1.96-2.12 (m, 1 H) 2.60- 2.76 (m, 1 H) 3.20-3.31 (m, 1 H) 3.51-3.61 (m,1 H) 3.62- 3.72 (m, 1 H) 3.73-3.89 (m, 2 H) 3.93-4.16 (m, 2 H) 5.37-5.57 (m, 1 H) 7.49-7.62 (m, 2 H) 7.69 (d, 1 H) 7.93-8.09 (m, 2 H) 8.25(d, 1 H) 9.18-9.36 (m, 1 H). 299

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(2R)- tetrahydrofuran-2-ylmethoxy]-N- {(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl]ethyl}benzamide LCMS (method 1): rt: 1.37 min, MS ES+ m/z = 521 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.65 (d, 3 H)1.69-1.78 (m, 1 H) 1.79-1.95 (m, 2 H) 1.96-2.09 (m, 1 H) 3.28 (m, 1 H)3.69 (m, 1 H) 3.79 (m, 1 H) 3.98-4.13 (m, 2 H) 4.14-4.29 (m, 1 H) 5.49(m, 1 H) 7.51-7.62 (m, 2 H) 7.69 (d, 1 H) 7.94-8.09 (m, 2 H) 8.25 (d, 1H) 9.28 (d, 1 H). 300

3-(5-cyclobutyl- 1,3-thiazol-2-yl)-5- [(2S)- tetrahydrofuran-2-ylmethoxy]-N- {(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl]ethyl}benzamide LCMS (method 1): rt: 1.41 min, MS ES+ m/z = 533 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.65 (d, 3 H) 1.75 (m, 1 H)1.80-1.95 (m, 3 H) 1.95- 2.06 (m, 2 H) 2.08-2.22 (m, 2 H) 2.36-2.48 (m,2 H) 3.61- 3.73 (m, 1 H) 3.75-3.90 (m, 2 H) 3.96-4.14 (m, 2 H) 4.15-4.27 (m, 1 H) 5.49 (m, 1 H) 7.51- 7.62 (m, 2 H) 7.68 (d, 1 H) 7.93-8.10(m, 2 H) 8.25 (d, 1 H) 9.29 (d, 1 H). 301

3-[5-(propan-2-yl)- 1,3-thiazol-2-yl]-5- [(2S)- tetrahydrofuran-2-ylmethoxy]-N- {(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl]ethyl}benzamide LCMS (method 1): rt: 1.37 min, MS ES+ m/z = 521 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.33 (d, 6 H) 1.65 (d, 3 H)1.69-1.77 (m, 1 H) 1.80-1.95 (m, 2 H) 1.97-2.11 (m, 1 H) 3.20-3.32 (m, 1H) 3.70 (m, 1 H) 3.79 (m, 1 H) 3.98-4.13 (m, 2 H) 4.16-4.26 (m, 1 H)5.49 (m, 1 H) 7.57 (m, 2 H) 7.69 (d, 1 H) 7.92-8.11 (m, 2 H) 8.25 (d, 1H) 9.28 (d, 1 H). 302

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(2S)- tetrahydrofuran-2- ylmethoxy]-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamide LCMS(method 1): rt: 1.30 min, MS ES+ m/z = 507 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.29 (t, 3 H) 1.65 (d, 3 H) 1.69- 1.80 (m, 1 H) 1.80-1.95(m, 2 H) 1.95-2.09 (m, 1 H) 2.90 (m, 2 H) 3.60-3.75 (m, 1 H) 3.79 (m, 1H) 3.98-4.13 (m, 2 H) 4.15-4.28 (m, 1 H) 5.37-5.59 (m, 1 H) 7.57 (m, 2H) 7.68 (t, 1 H) 7.92-8.09 (m, 2 H) 8.25 (d, 1 H) 9.29 (d, 1 H). 303

3-(5-methyl-1,3- thiazol-2-yl)-5-{[1- (2,2,2- trifluoroethyl)piperidin-4-yl]oxy}- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS (method 1): rt: 1.39 min, MS ES+ m/z = 574 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, 3 H) 1.69 (m, 2 H) 1.94(m, 2 H) 2.55-2.66 (m, 2 H) 2.79-2.94 (m, 2 H) 3.12- 3.27 (m, 2 H)4.52-4.67 (m, 1 H) 5.29 (m, 1 H) 7.46-7.59 (m, 2 H) 7.64 (d, 1 H) 7.90(t, 1 H) 9.05-9.21 (m, 3 H). 304

3-{[1-(2,2- difluoroethyl) piperidin-4-yl]oxy}- 5-(5-methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoroethyl) pyrimidin-5-yl]ethyl}benzamide LCMS (method 1): rt: 0.97 min, MS ES+ m/z = 556 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (m, 5 H) 1.84-2.10 (m, 2 H)2.62-3.01 (m, 4 H) 4.42-4.73 (m, 1 H) 5.29 (m, 1 H) 5.85-6.42 (m, 1 H)7.42- 7.70 (m, 3 H) 7.91 (s, 1 H) 9.12 (m, 3 H). 305

3-{[1-(2,2- difluoroethyl) piperidin-4-yl]oxy}-N- [(1R)-1-(6-methylpyridazin-3- yl)ethyl]-5-(5- methyl-1,3- thiazol-2-yl) benzamideLCMS (method 1): rt: 0.77 min, MS ES+ m/z = 502 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.58 (d, 3 H) 1.62-1.75 (m, 2 H) 1.88-2.03 (m, 2H) 2.59 (s, 3 H) 2.70-2.89 (m, 4 H) 3.33 (s, 2 H) 4.50-4.67 (m, 1 H)5.36 (m, 1 H) 6.14 (m, 1 H) 7.48-7.69 (m, 5 H) 7.92 (t, 1 H) 9.14 (d, 1H). 306

3-{[1-(2,2- difluoroethyl) piperidin-4-yl]oxy}-N- [(1R)-1-(5-methylpyrazin-2- yl)ethyl]-5-(5- methyl-1,3- thiazol-2-yl) benzamideLCMS (method 1): rt: 0.84 min, MS ES+ m/z = 502 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.54 (d, 3 H) 1.69 (br. s., 2 H) 1.94 (br. s., 2H) 2.47 (s, 3 H) 2.68-2.86 (m, 4 H) 3.21- 3.46 (m, 2 H) 4.48-4.66 (m, 1H) 5.22 (m, 1 H) 6.14 (m, 1 H) 7.48-7.57 (m, 2 H) 7.64 (d, 1 H) 7.91 (t,1 H) 8.44-8.60 (m, 2 H) 9.10 (d, 1 H). 307

3-{[1-(2,2- difluoroethyl)piperidin- 4-yl]oxy}-N- [(6-methylpyridazin-3-yl)methyl]-5-(5- methyl-1,3-thiazol-2- yl)benzamide LCMS (method 2):rt: 1.09 min, MS ES+ m/z = 488 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.68 (m, 2 H) 1.88-2.04 (m, 2 H) 2.55-2.64 (s, 3 H) 2.69- 2.85 (m,4 H) 3.33 (s, 2 H) 4.56 (m, 1 H) 4.73 (d, 2 H) 6.14 (m, 1 H) 7.43-7.58(m, 4 H) 7.64 (d, 1 H) 7.95 (t, 1 H) 9.39 (s, 1 H). 308

3-{[1-(2,2- difluoroethyl)piperidin- 4-yl]oxy}-5-(5-methyl-1,3-thiazol-2- yl)-N- {(1S)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS (method 1): rt: 0.98 min, MS ES+ m/z = 556 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (m, 5 H) 1.86-2.18 (m, 2 H)2.61-3.05 (m, 4 H) 4.35-4.80 (m, 1 H) 5.29 (m, 1 H) 5.85-6.45 (m, 1 H)7.44- 7.71 (m, 3 H) 7.91 (s, 1 H) 9.03- 9.27 (m, 3 H). 309

3-{[1-(2,2- difluoroethyl)piperidin- 4-yl]oxy}-N- [(1R)-1-(2-methylpyrimidin- 5-yl)ethyl]-5-(5- methyl-1,3-thiazol-2- yl)benzamideLCMS (method 1): rt: 0.78 min, MS ES+ m/z = 502 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.54 (d, 3 H) 1.67 (m, 2 H) 1.94 (m, 2 H) 2.59 (s, 3H) 2.69-2.84 (m, 4 H) 3.33 (br. s., 2 H) 4.50- 4.65 (m, 1 H) 5.09-5.24(m, 1 H) 6.14 (m, 1 H) 7.52 (m, 2 H) 7.64 (d, 1 H) 7.89 (t, 1 H) 8.71(s, 2 H) 9.05 (d, 1 H). 310

3-(5-methyl-1,3- thiazol-2-yl)-5-{[1- (2,2,2- trifluoroethyl)piperidin-4-yl]oxy}-N- {(1S)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS (method 1): rt: 1.39 min, MS ES+ m/z = 502 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) d [ppm] 1.60 (d, 3 H) 1.69 (br. s., 2 H)1.88-2.03 (m, 2 H) 2.62 (br. s., 2 H) 2.80-2.94 (m, 2 H) 3.10-3.26 (m, 2H) 4.51-4.70 (m, 1 H) 5.29 (m, 1 H) 7.54 (m, 2 H) 7.64 (d, 1 H) 7.90 (t,1 H) 9.04-9.24 (m, 3 H). 311

N-[(1R)-1-(6- methylpyridazin-3- yl)ethyl]-3-(5- methyl-1,3-thiazol-2-yl)-5-{[1- (2,2,2- trifluoroethyl) piperidin-4-yl]oxy}benzamide LCMS (method 1): rt: 1.15 min, MS ES+ m/z = 520 (M + H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 1.58 (d, 3 H) 1.64-1.79 (m, 2 H) 1.95(br. s., 2 H) 2.55- 2.68 (m, 5 H) 2.85 (m, 2 H) 3.10- 3.28 (m, 2 H)4.51-4.67 (m, 1 H) 5.36 (m, 1 H) 7.45-7.69 (m, 5 H) 7.93 (t, 1 H) 9.14(d, 1 H). 312

3-(5-methyl-1,3- thiazol-2-yl)-5-{[1- (2,2,2- trifluoroethyl)piperidin-4-yl]oxy}-N- {(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl]ethyl}benzamide LCMS (method 1): rt: 1.35 min, MS ES+ m/z = 574 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.65 (m, 5 H) 1.86-2.05 (m, 2 H)2.62 (br. s., 2 H) 2.86 (br. s., 2 H) 3.21 (m, 2 H) 4.51- 4.67 (m, 1 H)5.48 (m, 1 H) 7.50- 7.69 (m, 3 H) 7.94 (t, 1 H) 8.04 (d, 1 H) 8.25 (d, 1H) 9.29 (d, 1 H). 313

N-[(1R)-1-(5- methylpyrazin-2- yl)ethyl]-3-(5- methyl-1,3-thiazol-2-yl)-5-{[1- (2,2,2- trifluoroethyl) piperidin-4-yl]oxy}benzamide LCMS (method 1): rt: 1.25 min, MS ES+ m/z = 520 (M +H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.54 (d, 3 H) 1.69 (m, 2 H) 1.94(br. s., 2 H) 2.47 (s, 3 H) 2.56-2.70 (m, 2 H) 2.80-2.94 (m, 2 H) 3.20(q, 2 H) 4.50- 4.66 (m, 1 H) 5.22 (m, 1 H) 7.45- 7.57 (m, 2 H) 7.64 (d,1 H) 7.92 (t, 1 H) 8.48 (d, 1 H) 8.56 (d, 1 H) 9.09 (d, 1 H). 314

N-[(6- methylpyridazin-3- yl)methyl]-3-(5- methyl-1,3-thiazol-2-yl)-5-{[1- (2,2,2- trifluoroethyl) piperidin-4-yl]oxy}benzamide LCMS (method 1): rt: 1.11 min, MS ES+ m/z = 506 (M + H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 1.58-1.77 (m, 2 H) 1.88- 2.07 (m, 2 H)2.56-2.70 (m, 5 H) 2.79-2.94 (m, 2 H) 3.12- 3.29 (m, 2 H) 4.51-4.65 (m,1 H) 4.73 (d, 2 H) 7.48-7.58 (m, 4 H) 7.64 (d, 1 H) 7.95 (t, 1 H) 9.39(s, 1 H). 315

N-[(1R)-1-(2- methylpyrimidin- 5-yl)ethyl]-3-(5- methyl-1,3-thiazol-2-yl)-5-{[1- (2,2,2- trifluoroethyl) piperidin-4-yl]oxy}benzamide LCMS (method 1): rt: 1.17 min, MS ES+ m/z = 520 (M + H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 1.54 (d, 3 H) 1.68 (m, 2 H) 1.94 (m, 2 H)2.55-2.70 (m, 5 H) 2.78-2.94 (m, 2 H) 3.12- 3.28 (m, 2 H) 4.59 (br. s.,1 H) 5.16 (m, 1 H) 7.42-7.58 (m, 2 H) 7.64 (d, 1 H) 7.89 (t, 1 H) 8.71(s, 2 H) 9.05 (d, 1 H). 316

3-(5-chloro-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(3S)- tetrahydrofuran-3- ylmethoxy]benzamide LCMS (method1): rt: 1.11 min, MS ES+ m/z = 459 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.59 (d, 3 H) 1.64-1.79 (m, 1 H) 1.97-2.14 (m, 1 H) 2.59 (s, 3 H)2.63-2.77 (m, 1 H) 3.57 (dd, 1 H) 3.67 (m, 1 H) 3.81 (td, 2 H) 4.06 (dd,2 H) 5.36 (m, 1 H) 7.42-7.69 (m, 4 H) 7.90-8.06 (m, 2 H) 9.17 (d, 1 H).317

3-(5-chloro-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(3R)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.06 min, MS ES+ m/z = 445 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.59 (d, J = 7.07 Hz, 3 H) 1.91-2.08 (m, 1 H) 2.15-2.31 (m, 1 H)2.56-2.63 (s, 3 H) 3.71- 3.97 (m, 4 H) 5.22 (m, 1 H) 5.36 (m, 1 H)7.51-7.67 (m, 4 H) 7.91-8.07 (m, 2 H) 9.17 (d, 1 H). 318

3-(5-chloro-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3-yloxy]-N-{(1R)-1- [6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamideLCMS (method 1): rt: 1.26 min, MS ES+ m/z = 499 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.65 (d, 3 H) 1.93-2.08 (m, 1 H) 2.18-2.32 (m, 1H) 3.67-4.01 (m, 4 H) 5.23 (m, 1 H) 5.48 (m, 1 H) 7.49-7.66 (m, 2 H)7.90-8.09 (m, 3 H) 8.25 (d, 1 H) 9.31 (d, 1 H). 319

3-(5-chloro-1,3- thiazol-2-yl)-N- [(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(3R)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.15 min, MS ES+ m/z = 445 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.54 (d, 3 H) 1.91-2.06 (m, 1 H) 2.25 (m, 1 H) 2.47 (s, 3 H)3.70-3.97 (m, 4 H) 5.13- 5.30 (m, 2 H) 7.51-7.66 (m, 2 H) 7.90-8.06 (m,2 H) 8.49 (d, 1 H) 8.56 (d, 1 H) 9.12 (d, 1 H). 320

3-(5-chloro-1,3- thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3-yloxy]-N-{(1R)-1- [6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamideLCMS (method 1): rt: 1.26 min, MS ES+ m/z = 499 (M + H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 1.65 (d, 3 H) 1.89-2.10 (m, 1 H) 2.26 (m, 1 H)3.69- 3.99 (m, 4 H) 5.23 (m, 1 H) 5.48 (m, 1 H) 7.58 (dt, 2 H) 7.90-8.12 (m, 3 H) 8.25 (d, 1 H) 9.31 (d, 1 H). 321

3-(5-chloro-1,3- thiazol-2-yl)-N- [(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5-[(3S)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.16 min, MS ES+ m/z = 445 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.54 (d, 3 H) 1.94-2.09 (m, 1 H) 2.17-2.33 (m, 1 H) 2.47 (s, 3 H)3.71-3.97 (m, 4 H) 5.12-5.29 (m, 2 H) 7.56 (dt, 2 H) 7.91-8.04 (m, 2 H)8.49 (d, 1 H) 8.56 (d, 1 H) 9.12 (d, 1 H). 322

3-(5-chloro-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5-[(3S)- tetrahydrofuran-3- yloxy]benzamide LCMS (method 1):rt: 1.06 min, MS ES+ m/z = 445 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.59 (d, 3 H) 1.93-2.12 (m, 1 H) 2.26 (m, 1 H) 2.59 (s, 3 H)3.71-3.98 (m, 4 H) 5.23 (m, 1 H) 5.36 (m, 1 H) 7.48-7.66 (m, 4 H)7.92-8.06 (m, 2 H) 9.17 (d, 1 H). 323

3-(5-chloro-1,3- thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3-ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS (method 1): rt: 1.31 min, MS ES+ m/z = 513 (M +H)⁺. ¹H NMR (400 MHz, CHLORO- FORM-d) δ [ppm] 1.69 (m, 4 H) 1.98-2.17(m, 1 H) 2.59-2.78 (m, 1 H) 3.59-3.79 (m, 2 H) 3.80- 4.03 (m, 4 H)5.43-5.63 (m, 1 H) 7.36 (dd, 1 H) 7.47 (dd, 2 H) 7.60 (s, 1 H) 7.64-7.72(m, 1 H) 7.74-7.82 (m, 2 H). 324

3-(5-chloro-1,3- thiazol-2-yl)-N- [(1R)-1-(5- methylpyrazin-2-yl)ethyl]-5- (tetrahydro-2H- pyran-4- yloxy)benzamide LCMS (method 1):rt: 1.21 min, MS ES+ m/z = 459 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) d[ppm] 1.54 (d, 3 H) 1.62 (m, 2 H) 2.00 (m, 2 H) 2.47 (s, 3 H) 3.44-3.60(m, 2 H) 3.76-3.93 (m, 2 H) 4.77 (m, 1 H) 5.22 (m, 1 H) 7.51-7.67 (m, 2H) 7.88- 8.06 (m, 2 H) 8.43-8.60 (m, 2 H) 9.11 (d, 1 H). 325

3-(5-chloro-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3-yl)ethyl]-5- (tetrahydro-2H- pyran-4- yloxy)benzamide LCMS (method 1):rt: 1.11 min, MS ES+ m/z = 459 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 1.59 (m, 5 H) 1.91-2.06 (m, 2 H) 2.59 (s, 3 H) 3.52 (m, 2 H) 3.86(m, 2 H) 4.73-4.85 (m, 1 H) 5.36 (m, 1 H) 7.51-7.65 (m, 4 H) 7.90-8.07(m, 2 H) 9.16 (d, 1 H). 326

3-(5-chloro-1,3- thiazol-2-yl)-5- (tetrahydro-2H- pyran-4-yloxy)-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamide LCMS(method 1): rt: 1.31 min, MS ES+ m/z = 513 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.65 (m, 5 H) 1.99 (m, 2 H) 3.52 (m, 2 H) 3.86 (m, 2 H)4.69-4.85 (m, 1 H) 5.48 (m, 1 H) 7.57-7.68 (m, 2 H) 7.90- 8.10 (m, 3 H)8.25 (d, 1 H) 9.30 (d, 1 H). 327

3-[(3- methyloxetan-3- yl)methoxy]-5-(5- methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide LCMS(method 1): rt: 1.25 min, MS ES+ m/z = 493 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.39 (s, 3 H) 1.61 (d, 3 H) 4.19 (s, 2 H) 4.33 (d, 2 H)4.54 (d, 2 H) 5.30 (s, 1 H) 7.52-7.72 (m, 3 H) 7.94 (t, 1 H) 9.12 (s, 2H) 9.19 (d, 1 H). 328

3-(2-hydroxy-2- methylpropoxy)-5- (5-methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl} benzamide LCMS(method 1): rt: 1.18 min, MS ES+ m/z = 481 (M + H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 1.23 (s, 6 H) 1.61 (d, 3 H) 3.84 (s, 2 H) 4.70 (s, 1 H)5.30 (m, 1 H) 7.46-7.59 (m, 2 H) 7.64 (d, 1 H) 7.92 (t, 1 H) 9.12 (s, 2H) 9.19 (d, 1 H).

Example 3293-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,as a mixture of two diastereoisomers

Example 329 (69 mg) was prepared from Intermediate 5BX in analogy to theprocedure described for Example 232.

LCMS (method 1): rt: 1.30 min, MS ES+ m/z=507 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.24-1.32 (s, 3 H) 1.61 (d, 3 H)1.65-1.74 (m, 1 H) 1.93 (m, 3 H) 3.70-3.84 (m, 2 H) 3.95 (s, 2 H)5.20-5.40 (m, 1 H) 7.49-7.59 (m, 2 H) 7.64 (d, 1 H) 7.92 (t, 1 H)9.06-9.23 (m, 3 H).

Example 329 (54.5 mg, 108 μmol) was separated into two diastereoisomersby preparative chiral HPLC (method A, 54.5 mg in 2.5 ml ethanol) to giveExample 330 (Diastereoisomer 1, 16 mg, rt: 5.6-7.4 min) and Example 331(Diastereoisomer 2, 16 mg, rt: 8.0-10.1 min).

Example 330 Diastereoisomer 1;3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method A, rt: 2.61 min

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 1.28 (s, 3 H) 1.61 (d, 3 H) 1.65-1.75(m, 1H) (m, 3 H) 3.70-3.85 (m, 2 H) 3.95 (d, 2 H) 5.30 (m, 1 H) 7.55 (m,2 H) 7.64 (d, 1 H) 7.92 (t, 1 H) 9.07-9.23 (m, 3 H).

Example 331 Diastereoisomer 2;3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method A, rt: 3.16 min

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 1.28 (s, 3 H) 1.61 (d, 3 H) 1.65-1.77(m, 1 H) 1.93 (m, 3 H) 3.70-3.86 (m, 2 H) 3.95 (s, 2 H) 5.30 (m, 1 H)7.55 (m, 2 H) 7.64 (d, 1 H) 7.92 (t, 1 H) 9.05-9.24 (m, 3 H).

Example 3323-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,as a Mixture of Two Diastereoisomers

Example 332 (1070 mg) was prepared from Intermediate 5BY in analogy tothe procedure described for Example 232.

LCMS (method 1): rt: 1.32 min, MS ES+ m/z=507 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.21 (s, 3 H) 1.55-1.74 (m, 4 H) 1.93(m, 1 H) 3.39 (d, 1 H) 3.71 (d, 1 H) 3.74-3.88 (m, 2 H) 3.96 (s, 2 H)5.30 (m, 1 H) 7.47-7.71 (m, 3 H) 7.92 (t, 1 H) 9.07-9.25 (m, 3 H).

Example 332 (1000 mg, 1.97 mmol) was separated into two diastereoisomersby preparative chiral HPLC (method B, 1000 mg in 7 ml DCM/methanol(1:1)) to give Example 333 (Diastereoisomer 1, 294 mg, rt: 6.0-8.0 min)and Example 334 (Diastereoisomer 2, 276 mg, rt: 9.0-10.0 min).

Example 333 Diastereoisomer 1;3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method B, rt: 2.89 min

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 1.21 (s, 3H) 1.61 (m, 4H) 1.88-2.03(m, 1H) 3.39 (d, 1 H) 3.71 (d, 1 H) 3.81 (td, 2 H) 3.96 (s, 2 H) 5.30(m, 1 H) 7.48-7.60 (m, 2 H) 7.64 (d, 1 H) 7.92 (t, 1 H) 9.04-9.24 (m, 3H).

Example 334 Diastereoisomer 2;3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method B, rt: 4.26 min

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 1.21 (s, 3 H) 1.51-1.74 (m, 4 H)1.86-2.01 (m, 1 H) 3.39 (d, 1 H) 3.71 (d, 1 H) 3.80 (td, 2 H) 3.96 (s, 2H) 5.30 (m, 1 H) 7.46-7.59 (m, 2 H) 7.64 (d, 1 H) 7.92 (t, 1 H)9.06-9.25 (m, 3 H).

Example 3353-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,as a mixture of two diastereoisomers

Example 335 (760 mg) was prepared from Intermediate 5BZ in analogy tothe procedure described for example 232.

LCMS (method 1): rt: 1.09 min, MS ES+ m/z=520 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.60 (d, 3 H) 2.07 (m, 2 H) 2.18-2.43(m, 2 H) 2.82 (s, 3 H) 3.37-3.51 (m, 1 H) 3.60-3.75 (m, 1 H) 4.96-5.13(m, 1 H) 5.20-5.36 (m, 1 H) 7.52-7.70 (m, 3 H) 7.94 (t, 1 H) 9.04-9.23(m, 3 H).

Example 335 (700 mg, 1.35 mmol) was separated into two diastereoisomersby preparative chiral HPLC (method E, 700 mg in 6 ml DCM/methanol (1:1))to give Example 336 (Diastereoisomer 1, 150 mg, rt: 7.00-9.00 min) andExample 337 (Diastereoisomer 2, 140 mg, rt: 10.00-12.60 min). Example336 Diastereoisomer 1;3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method E, rt: 2.11 min

¹H NMR (600 MHz, DMSO-d₆) δ [ppm] 1.61 (d, 3 H) 2.07 (m, 2 H) 2.21-2.32(m, 1 H) 2.33-2.43 (m, 1 H) 2.82 (s, 3 H) 3.39-3.50 (m, 1 H) 3.64-3.75(m, 1 H) 5.05 (m, 1 H) 5.30 (m, 1 H) 7.56-7.72 (m, 3 H) 7.94 (s, 1 H)9.06-9.23 (m, 3 H).

Example 337 Diastereoisomer 2;3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method E, rt: 2.88 min

¹H NMR (600 MHz, DMSO-d₆) δ [ppm] 1.61 (d, 3 H) 2.01-2.14 (m, 2 H)2.21-2.30 (m, 1 H) 2.33-2.42 (m, 1 H) 2.82 (s, 3 H) 3.37-3.49 (m, 1 H)3.63-3.74 (m, 1 H) 4.95-5.12 (m, 1 H) 5.22-5.37 (m, 1 H) 7.55-7.71 (m, 3H) 7.94 (t, 1 H) 9.12 (s, 3 H).

Example 338 3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,as a mixture of cis isomers

Example 338 (154 mg) was prepared from Intermediate 5CB in analogy tothe procedure described for example 232.

LCMS (method 1): rt: 1.18 min, MS ES+ m/z=481 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.11 (d, 3 H) 1.21 (dd, 3 H) 1.61 (d,3 H) 3.68-3.86 (m, 1 H) 4.34-4.48 (m, 1 H) 4.87 (dd, 1 H) 5.20-5.38 (m,1 H) 7.53 (m, 2 H) 7.64 (d, 1 H) 7.89 (s, 1 H) 9.06-9.22 (m, 3 H).

Example 338 (646 mg, 1.34 mmol) was separated into two diastereoisomersby preparative chiral HPLC (method D, 646 mg in 5 ml DCM/methanol (1:1))to give Example 339 (Cis Isomer 1, 197 mg, rt: 9.7-10.8 min) and Example340 (Cis Isomer 2, 198 mg, rt: 11.7-13.4 min).

Example 339 Cis Isomer 1;3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method D, rt: 5.73 min

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.09-1.12 (m, 6 H) 1.21 (d, 3 H) 1.61(d, J=7.35 Hz, 3 H) 3.69-3.85 (m, 1 H) 4.43 (m, 1 H) 4.86 (d, 1 H) 5.29(m, 1 H) 7.47-7.58 (m, 2 H) 7.64 (d, 1 H) 7.89 (t, 1 H) 9.05-9.22 (m, 3H).

Example 340 Cis Isomer 2;3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method D, rt: 6.97 min

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.09-1.14 (m, 3 H) 1.20 (d, 3 H) 1.61(d, 3 H) 3.64-3.87 (m, 1 H) 4.33-4.50 (m, 1 H) 4.87 (d, 1 H) 5.18-5.38(m, 1 H) 7.53 (m, 2 H) 7.64 (d, 1 H) 7.89 (t 1 H) 9.05-9.24 (m, 3 H).

Example 3413-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,as a Mixture of Two Stereoisomers

A mixture of Intermediate 109 (100 mg, 187 μmol), formaldehyde (140 μl,37% solution, 1.9 mmol), acetic acid (107 μl, 100%, 1.9 mmol) in1,2-dichlorethane (1.5 mL) was stirred at RT for 30 min. Sodiumtriacetoxyborohydride (113 mg, 1.9 mmol) was added and the mixturestirred at RT for 17 h. A saturated aqueous NaHCO₃-solution was addedand the aqueous layer extracted twice with DCM. The combined organiclayers were evaporated to dryness under reduced pressure and the residuepurified by column chromatography to give 57 mg (55% yield) of the titlecompound.

LCMS (method 1): rt: 0.92 min, MS ES+ m/z=548 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, 6 H) 1.91 (br. s., 2 H)1.96-2.05 (m, 2 H) 2.16 (s, 6 H) 2.55-2.64 (m, 2 H) 2.71-2.86 (m, 2 H)2.96-3.09 (m, 2 H) 3.58-3.70 (m, 2 H) 3.72-3.86 (m, 2 H) 3.90-4.05 (m, 4H) 4.58-4.69 (m, 1 H) 4.71-4.85 (m, 1 H) 5.20-5.37 (m, 2 H) 7.51-7.69(m, 6 H) 7.94 (s, 2 H) 9.12 (s, 4 H) 9.17-9.25 (m, 2 H).

Example 341 (281 mg, 0.51 mmol) was separated into two stereoisomers bypreparative HPLC (method F, 281 mg in 4 ml DMSO) to give Example 342(stereoisomer 1, 125 mg, rt: 7.0-8.0 min) and Example 343 (stereoisomer2, 100 mg, rt: 9.0-11.0 min).

Example 342 Stereoisomer 1;3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical HPLC, method F, rt: 2.38 min

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, 3 H) 1.91 (br. s., 2 H) 2.17(s, 3 H) 3.05 (d, 2 H) 3.65 (d, 2 H) 3.98 (d, 2 H) 4.63 (br. s., 1 H)5.29 (m, 1 H) 7.51-7.70 (m, 3 H) 7.94 (t, 1 H) 9.12 (s, 2 H) 9.19 (d, 1H).

Example 343 Stereoisomer 2;3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical HPLC, method F, rt: 2.89 min

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.62 (d, 3 H) 2.00 (br. s., 2 H) 2.14(s, 3 H) 2.54-2.64 (m, 2 H) 2.69-2.82 (m, 2 H) 3.80 (m, 2 H) 3.95 (m, 2H) 4.77 (br. s., 1H) 5.21-5.38 (m, 1 H) 7.49-7.72 (m, 3 H) 7.94 (t, 1 H)9.13 (s, 2 H) 9.17-9.26 (m, 1 H).

Example 3443-[(7-isopropyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,as a mixture of two stereoisomers

Example 344 (66.7 mg) was prepared from Intermediate 109 (100 mg, 187μmol) in analogy to the procedure described for Example 341.

LCMS (method 1): rt: 0.95 min, MS ES+ m/z=576 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 0.99 (m, 12 H) 1.61 (d, 6 H) 1.92 (br.s., 2 H) 1.96-2.05 (m, 2 H) 2.60-2.78 (m, 6 H) 2.93-3.08 (m, 2 H) 3.62(m, 2 H) 3.80 (m, 2 H) 3.91 (m, 4 H) 4.54-4.67 (m, 1 H) 4.71-4.84 (m, 1H) 5.29 (m, 2 H) 7.50-7.67 (m, 6 H) 7.93 (s, 2 H) 9.12 (s, 4 H)9.17-9.30 (m, 2 H).

Example 345 methyl9-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]-3-oxa-7-azabicycle[3.3.1]nonane-7-carboxylate,as a mixture of two stereoisomers

To a mixture of Intermediate 109 (100 mg, 187 μmol) and DIPEA (160 μl,940 μmol) in DCM (4.6 mL) was added methyl carbonochloridate (43 μl, 560μmol), and the mixture was stirred at RT for 17 h. Water and DCM wereadded, the phases separated and the aqueous layer extracted with DCM.The combined organice layers dried with Na₂SO₄, filtered and evaporatedto dryness under reduced pressure and the residue purified by columnchromatography to give 75 mg (68% yield) of the title compound.

LCMS (method 1): rt: 1.20 min, MS ES+ m/z=592 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 1.61 (d, 6 H) 1.81-1.95 (m, 2 H) 1.99(m, 2 H) 3.21-3.32 (m, 2 H) 3.35-3.46 (m, 2 H) 3.58 (d, 6 H) 3.64-3.81(m, 4 H) 3.97 (m, 6 H) 4.16-4.43 (m, 2 H) 4.84-4.99 (m, 2 H) 5.21-5.37(m, 2 H) 7.54-7.72 (m, 6 H) 7.95 (d, 2 H).

Example 346 Tert-butyl(2R)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate

To a solution of Intermediate 5CE (28.21 g, 45.4 mmol), Intermediate VI(11.4 g, 50.0 mmol) and DIPEA (31.6 mL, 181.8 mmol) in ethyl acetate(400 mL) was added T3P (32 mL, 54.5 mmol). The reaction mixture wasstirred at RT for 15 h. Further Intermediate VI (1 g, 4.55 mmol), DIPEA(3 mL, 17.7 mmol) and T3P (4 mL, 6.82 mmol) were added and the reactionmixture stirred at RT for 1 h. The reaction mixture was washed withsaturated NaHCO₃, brine and the organic layer dried (MgSO₄), filteredand concentrated at reduced pressure. The crude product was purified byBiotage Isolera™ chromatography (eluting with 0-100% EtOAc in heptane ona pre-packed KP-SiO₂ column) to give 14.8 g (49% yield) of the titlecompound as white foam.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.96-7.88 (m, 1H),7.58-7.53 (m, 1H), 7.54-7.52 (m, 1H), 7.42-7.39 (m, 1H), 6.79 (br s,1H), 5.43-5.31 (m, 1H), 4.15-3.76 (m, 6H), 3.64-3.54 (m, 1H), 3.07-2.77(m, 2H), 2.53 (d, J=1.1 Hz, 3H), 1.72 (d, J=7.2 Hz, 3H), 1.48 (s, 9H).

LCMS (Analytical Method F) Rt=4.02 min, MS (ESIpos): m/z=608 (M+H)⁺.

Example 3473-(5-Methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of Example 346 (14.7 g, 22.3 mmol) in DCM (100 mL) wasadded TFA (17.1 mL). The resulting solution was stirred for 16 h at RT.The reaction mixture was basified with 2M sodium hydroxide (100 mL) thensaturated aqueous sodium bicarbonate solution to pH 8. The organic layerwas separated and the aqueous layer extracted with further DCM. Thecombined organics were washed with brine, dried (sodium sulfate),filtered and concentrated at reduced pressure to give 10.5 g (93% yield)of the title compound as pale yellow solid. The bulk sample was used toprepare Example 348 without further purification.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.96 (s, 2H), 7.83-7.79 (m, 1H),7.47 (dd, J=2.3, 1.5 Hz, 1H), 7.46-7.45 (m, 1H), 7.40-7.37 (m, 1H),7.33-7.28 (m, 1H), 5.42-5.32 (m, 1H), 4.14-3.53 (m, 6H), 3.21-3.13 (m,1H), 3.02-2.93 (m, 2H), 2.86-2.74 (m, 1H), 2.49 (d, J=1.0 Hz, 3H), 1.70(d, J=7.2 Hz, 3H).

LCMS (Method A) Rt=1.04 min, MS (ESIpos): m/z=508 (M+H)⁺.

An aliquot of Example 347 (150 mg) was further purified by SCXchromatography eluting with methanol then 7N ammonia in methanol. Therelevant fractions were concentrated at reduced pressure thenlyophilised from acetonitrile/water to give 145 mg of the title compoundfor profiling and chiral analysis.

HPLC Chiral Analysis (Method 11): 99.3% e.e. Rt=10.51 min.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.94-7.80 (m, 1H),7.55 (dd, J=2.4, 1.5 Hz, 1H), 7.52-7.49 (m, 1H), 7.41 (dd, J=2.3, 1.5Hz, 1H), 6.78 (d, J=6.6 Hz, 1H), 5.47-5.27 (m, 1H), 4.16-3.64 (m, 5H),3.13-2.69 (m, 4H), 2.52 (d, J=1.1 Hz, 3H), 1.71 (d, J=7.1 Hz, 3H).

LCMS (Analytical Method F) Rt=2.16 min, MS (ESIpos): m/z=508 (M+H)⁺.

Example 3483-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Example 347 (10.3 g, 19.3 mmol), formaldehyde (7.2 mL, 37% solution inwater, 96.4 mmol) and acetic acid (1.10 mL) were combined in methanol(250 mL) and STAB (12.3 g, 57.8 mmol) was added portionwise. Theresulting solution was stirred at RT for 2 h then concentrated underreduced pressure. The residue was taken up in saturated NaHCO₃ (100 mL)solution and extracted with DCM (3×100 mL). The combined organic phasewas dried (MgSO₄), filtered and concentrated at reduced pressure. Thecrude material was purified by Biotage Isolera™ chromatography (elutingwith 0-10% MeOH in DCM on a 340 g pre-packed KP-SiO₂ column). Therelevant fractions were concentrated then lyophilised fromacetonitrile/water to give 6.75 g (67% yield) of the title compound aswhite solid.

HPLC Chiral Analysis (Method 12): 100% e.e. Rt=5.09 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87-7.85 (m, 1H),7.57 (dd, J=2.4, 1.4 Hz, 1H), 7.52-7.50 (m, 1H), 7.40 (dd, J=2.3, 1.6Hz, 1H), 6.67 (d, J=6.5 Hz, 1H), 5.42-5.29 (m, 1H), 4.12 (dd, J=9.9, 6.1Hz, 1H), 4.04 (dd, J=9.9, 4.1 Hz, 1H), 4.00-3.93 (m, 2H), 3.79-3.72 (m,1H), 2.85-2.80 (m, 1H), 2.72-2.65 (m, 1H), 2.53 (d, J=1.1 Hz, 3H), 2.33(s, 3H), 2.24-2.15 (m, 1H), 2.08-2.00 (m, 1H), 1.71 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method F) Rt=2.15 min, MS (ESIpos) m/z=522 (M+H)⁺.

Example 349 Tert-butyl(2S)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate

Intermediate 5CD (800 mg, 1.84 mmol), Intermediate VI (460 mg, 2.02mmol) and DIPEA (0.96 mL, 5.51 mmol) were combined in DCM (7 mL) andHATU (1050 mg, 2.76 mmol) was added. The reaction mixture was stirred atRT for 2 h then diluted with DCM and washed with water. The aqueousphase was extracted with further DCM and the combined organics dried(MgSO₄), filtered and concentrated at reduced pressure. The crudematerial was purified by Biotage Isolera™ chromatography (eluting with0-10% MeOH in DCM on a 50 g pre-packed KP-SiO₂ column) to give 1.6 g(100% yield) of the title compound as a colourless viscous oil.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.88 (s, 1H), 7.55(d, J=2.2 Hz, 1H), 7.49 (d, J=1.1 Hz, 1H), 7.37 (s, 1H), 7.11 (d, J=6.1Hz, 1H), 5.45-5.30 (m, 1H), 4.21-3.49 (m, 10H), 2.51 (d, J=0.9 Hz, 3H),1.71 (d, J=7.1 Hz, 3H), 1.47 (s, 9H).

LC-MS (Method A) Rt=1.32 min, MS (ESIpos) m/z=608 (M+H)⁺.

Example 3503-(5-Methyl-1,3-thiazol-2-yl)-5-[(2S)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of Example 349 (1.6 g, 1.98 mmol) in DCM (16 mL) was addedTFA (3 mL). The resulting solution was stirred for 4 h at RT thenneutralised with saturated aqueous sodium bicarbonate solution. Theorganic layer was separated and the aqueous layer extracted with furtherDCM. The combined organics were dried (MgSO₄), filtered and concentratedat reduced pressure to give 0.87 g (87% yield) of the title compound aspale yellow solid.

HPLC Chiral Analysis (Method 11): 100% e.e. Rt=9.04 min.

¹H NMR (500 MHz, Chloroform-d): δ 8.93 (s, 2H), 7.86 (s, 1H), 7.56-7.53(m, 2H), 7.52-7.48 (m, 1H), 7.42-7.37 (m, 1H), 6.81 (d, J=6.6 Hz, 1H),5.40-5.31 (m, 1H), 4.07 (dd, J=9.9, 6.0 Hz, 1H), 4.01 (dd, J=9.9, 4.2Hz, 2H), 3.98-3.86 (m, 2H), 3.75-3.66 (m, 1H), 3.06-2.99 (m, 1H),2.98-2.90 (m, 1H), 2.90-2.84 (m, 1H), 2.78 (dd, J=11.9, 10.4 Hz, 1H),2.52 (s, 3H), 1.71 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method F) Rt=2.14 min, MS (ESIpos) m/z=508 (M+H)⁺.

Example 3513-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Example 350 (238 mg, 0.47 mmol), formaldehyde (37% aqueous solution,0.07 mL, 0.94 mmol) and acetic acid (0.03 mL, 0.47 mmol) in DCE (3 mL)were stirred for 15 min before addition of STAB (149 mg, 0.70 mmol)portionwise. The reaction mixture was stirred at RT for 2 h then dilutedwith DCM and washed with saturated aqueous sodium bicarbonate. Theorganic phase was separated, dried (MgSO₄), filtered and concentrated atreduced pressure. The crude material was purified by high pH preparativeHPLC (Method A) to give 144 mg (59% yield) of the title compound, whichwas freeze-dried to a white powder.

HPLC Chiral Analysis (Method 12): 92.4% e.e. Rt=4.5 min.

¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.86 (s, 1H), 7.56(d, J=1.4 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.41 (s, 1H), 6.71 (d, J=6.1Hz, 1H), 5.43-5.30 (m, 1H), 4.17-3.90 (m, 4H), 3.80-3.65 (m, 1H),3.10-2.75 (m, 4H), 2.53 (d, J=1.0 Hz, 3H), 1.72 (d, J=7.1 Hz, 3H).

LC-MS (Analytical Method F) Rt=2.06 min, MS (ESIpos) 522 (M+H)⁺.

Example 347 and Example 350 can also be prepared as a mixture ofdiastereoisomers (Example 352) and subsequently separated by HPLC ChiralPurification (Method 11).

Example 3523-(5-Methyl-1,3-thiazol-2-yl)-5-[morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,Formed as a Mixture of Example 347 (Diastereoisomer 1) and Example 350(Diastereoisomer 2)

To a solution of Intermediate 114 (197 mg, 0.30 mmol) dissolved in DCM(5 mL) was added TFA (0.5 mL, 6.0 mmol) and the reaction stirred at RTovernight. The reaction mixture was neutralised with saturated NaHCO₃solution. The organic phase was collected and the aqueous phaseextracted with DCM (2×5 mL). The combined organic phases were dried(MgSO₄), filtered and concentrated at reduced pressure to give 177.0 mg(100% yield) of the title compound as a foam.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.91-8.87 (m, 2H), 7.74-7.69 (m, 1H),7.40-7.31 (m, 3H), 7.26-7.22 (m, 1H), 5.34-5.26 (m, 1H), 4.13-3.97 (m,3H), 3.96-3.80 (m, 2H), 3.36-3.26 (m, 1H), 3.19-3.01 (m, 2H), 3.00-2.90(m, 1H), 2.44-2.40 (m, 3H), 1.66-1.62 (m, 3H).

LC-MS (Method A) Rt=0.98 min, MS (ESIpos): m/z=508 (M+H)⁺.

Example 3473-(5-Methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

HPLC Chiral Purification (Method 11) was performed on 60 mg of Example352 diastereoisomer mixture to give 22 mg of the title compound.

HPLC Chiral Analysis (Method 11): 95.4% e.e. Rt=10.81 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.92 (s, 2H), 7.85 (t, J=1.3 Hz,1H), 7.53 (dd, J=2.3, 1.5 Hz, 2H), 7.50-7.48 (m, 1H), 7.40-7.35 (m, 1H),6.90 (d, J=6.6 Hz, 1H), 5.39-5.29 (m, 1H), 4.06 (dd, J=9.9, 6.1 Hz, 1H),3.98 (dd, J=9.9, 4.2 Hz, 3H), 3.96-3.91 (m, 1H), 3.91-3.85 (m, 1H),3.73-3.64 (m, 1H), 3.04-2.97 (m, 1H), 2.96-2.82 (m, 2H), 2.76 (dd,J=12.0, 10.4 Hz, 1H), 2.51 (d, J=1.0 Hz, 3H), 1.68 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method F) Rt=2.08 min, MS (ESIpos): m/z=508 (M+H)⁺.

Example 3503-(5-Methyl-1,3-thiazol-2-yl)-5-[(2S)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

HPLC Chiral Purification (Method 11) was performed on 60 mg of Example352 diastereoisomer mixture to give 13.8 mg of the title compound.

HPLC Chiral Analysis (Method 11): 100% e.e. Rt=9.39 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87-7.83 (m, 1H),7.52 (dd, J=2.3, 1.5 Hz, 2H), 7.50-7.48 (m, 1H), 7.40-7.35 (m, 1H), 6.93(d, J=6.7 Hz, 1H), 5.39-5.30 (m, 1H), 4.06 (dd, J=9.9, 6.0 Hz, 4H), 4.00(dd, J=9.9, 4.2 Hz, 1H), 3.97-3.92 (m, 1H), 3.92-3.86 (m, 1H), 3.74-3.65(m, 1H), 3.05-2.98 (m, 1H), 2.97-2.83 (m, 2H), 2.77 (dd, J=11.9, 10.5Hz, 1H), 2.51 (d, J=1.0 Hz, 3H), 1.69 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method F) Rt=2.08 min, MS (ESIpos): m/z=508 (M+H)⁺.

Example 348 and Example 351 can also be prepared as a mixture ofdiastereoisomers (Example 353) and subsequently separated by HPLC ChiralPurification (Method 12).

Example 3533-{[4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,formed as a mixture of Example 348 (Diastereoisomer 2) and Example 351(Diastereoisomer 1)

The Example 347 and Example 350 mixture (94.4 mg, 0.19 mmol),formaldehyde (37% solution in water, 70 μL, 0.93 mmol) and acetic acid(100 μL) were combined in methanol (2 mL) and STAB (118 mg, 0.56 mmol)was added. The resulting solution was stirred at RT for 2 h before beingconcentrated at reduced pressure. The residue was taken up in saturatedNaHCO₃ (5 mL) solution then extracted with DCM (3×5 mL). The combinedorganic phase was dried (MgSO₄), filtered and concentrated at reducedpressure. The compound was freeze-dried from acetonitrile/water to give78.7 mg (81% yield) of the title compound as white powder.

¹H NMR (500 MHz, CDCl₃): δ [ppm] 8.93 (s, 2H), 7.88-7.84 (m, 1H), 7.57(dd, J=2.4, 1.4 Hz, 1H), 7.54-7.50 (m, 1H), 7.42-7.38 (m, 1H), 6.62 (d,J=6.4 Hz, 1H), 5.40-5.31 (m, 1H), 4.16-4.08 (m, 1H), 4.08-4.01 (m, 1H),4.00-3.92 (m, 2H), 3.80-3.71 (m, 1H), 2.86-2.79 (m, 1H), 2.71-2.65 (m,1H), 2.53 (d, J=1.1 Hz, 3H), 2.33 (s, 3H), 2.24-2.15 (m, 1H), 2.09-2.00(m, 1H), 1.71 (d, J=7.2 Hz, 3H).

LC-MS (Analytical Method D) Rt=3.17 min, MS (ESIpos): m/z=522 (M+H)⁺.

Example 3483-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

HPLC Chiral Purification (Method 12) was performed on 52.4 mg of Example353 diastereoisomer mixture to give 22.9 mg (44% yield) of the titlecompound.

HPLC Chiral Analysis (Method 11): 96.4% e.e. Rt=5.15 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.87 (s, 1H), 7.58(dd, J=2.4, 1.4 Hz, 1H), 7.52 (d, J=1.1 Hz, 1H), 7.41 (s, 1H), 6.71 (s,1H), 5.36 (m, 1H), 4.17-4.10 (m, 1H), 4.09-4.02 (m, 2H), 3.97 (dd,J=11.6, 1.6 Hz, 1H), 3.82 (t, J=11.0 Hz, 1H), 2.91 (d, J=10.9 Hz, 1H),2.76 (d, J=10.7 Hz, 1H), 2.53 (d, J=1.1 Hz, 3H), 2.39 (s, 3H), 2.28 (s,1H), 2.14 (s, 1H), 1.72 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method F) Rt=2.11 min, MS (ESIpos): m/z=522 (M+H)⁺.

Example 3513-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

HPLC Chiral Purification (Method 12) was performed on 52.4 mg of Example353 diastereoisomer mixture to give 21.6 mg (41% yield) of the titlecompound.

HPLC Chiral Analysis (Method 11): 100% e.e. Rt=4.58 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.87 (s, 1H), 7.58(dd, J=2.3, 1.4 Hz, 1H), 7.52 (d, J=1.1 Hz, 1H), 7.41 (s, 1H), 6.71 (s,1H), 5.36 (m, 1H), 4.16-4.01 (m, 3H), 4.00-3.93 (m, 1H), 3.81 (t, J=11.0Hz, 1H), 2.91 (d, J=11.0 Hz, 1H), 2.76 (d, J=10.5 Hz, 1H), 2.53 (d,J=1.0 Hz, 3H), 2.39 (s, 3H), 2.28 (s, 1H), 2.15 (s, 1H), 1.72 (d, J=7.2Hz, 3H).

LCMS (Analytical Method D) Rt=3.31 min, MS (ESIpos): m/z=522 (M+H)⁺.

Intermediate 132 was formed as a mixture of two diastereoisomers. SFCChiral Purification (Method 13) provided diastereoisomer 1 (Example 354)and diastereoisomer 2 (Example 355).

Example 354 Diastereoisomer 1;3-(Fluoropiperidin-3-yl)methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral Purification (Method 13) on 55.2 mg of Intermediate 132followed by SCX-2 cartridge purification gave 14 mg of the titlecompound.

SFC Chiral Analysis (Method 13): 100% e.e. Rt=2.17 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.97 (s, 2H), 7.84 (s, 1H), 7.53(s, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 7.02 (s, 1H), 5.36 (q, J=7.0 Hz,1H), 4.23-3.99 (m, 2H), 3.43-3.22 (m, 1H), 3.09 (d, J=12.8 Hz, 1H), 2.95(dd, J=29.1, 13.9 Hz, 1H), 2.73 (s, 1H), 2.52 (s, 3H), 2.09-2.02 (m,1H), 1.94-1.78 (m, 3H), 1.73 (d, J=7.1 Hz, 3H), 1.67-1.60 (m, 1H).

LCMS (Analytical Method F) Rt=2.14 min, MS (ESIpos): m/z=524.4 (M+H)⁺.

Example 355 Diastereoisomer 2;3-(Fluoropiperidin-3-yl)methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral Purification (Method 13) on 55.2 mg of Intermediate 132followed by

SCX-2 cartridge purification gave 15 mg of the title compound.

SFC Chiral Analysis (Method 13): 98.2% e.e. Rt=3.26 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.90 (s, 2H), 7.74 (s, 1H), 7.42(s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 6.97 (s, 1H), 5.40-5.20 (m, 1H),4.15-3.90 (m, 2H), 3.38-3.19 (m, 1H), 3.06 (d, J=11.3 Hz, 1H), 2.88 (dd,J=29.9, 13.7 Hz, 1H), 2.68 (t, J=11.1 Hz, 1H), 2.43 (s, 3H), 2.05-1.90(m, 2H), 1.87-1.73 (m, 2H), 1.65 (d, J=7.0 Hz, 3H), 1.60-1.55 (m, 1H).

LCMS (Analytical Method F) Rt=2.12 min, MS (ESIpos): m/z=524.4 (M+H)⁺.

Intermediate 147 was formed as a mixture of two diastereoisomers. SFCChiral Purification (Method 14) provided diastereoisomer 1 (Example 356)and diastereoisomer 2 (Example 357).

Example 356 Diastereoisomer 1;3-{[3-fluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral Purification (Method 14) on 46 mg of Intermediate 147 gave 11mg of the title compound.

SFC Chiral Analysis (Method 14): 100% e.e. Rt=2.56 min.

¹H NMR (500 MHz, Methanol-d4): δ [ppm] 9.02 (s, 2H), 7.95 (s, 1H), 7.66(s, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 5.34 (q, J=7.1 Hz, 1H), 4.31-4.11(m, 2H), 3.03-2.88 (m, 1H), 2.70 (d, J=11.0 Hz, 1H), 2.54 (s, 3H), 2.43(dd, J=26.8, 12.3 Hz, 1H), 2.31 (s, 3H), 2.22 (t, J=10.6 Hz, 1H),2.00-1.86 (m, 2H), 1.77 (d, J=11.8 Hz, 1H), 1.70 (d, J=7.1 Hz, 3H),1.68-1.63 (m, 1H).

LCMS (Analytical Method F) Rt=2.18 min, MS (ESIpos): m/z=538 (M+H)⁺.

Example 357 Diastereoisomer 2;3-{[3-fluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral Purification (Method 14) on 46 mg of Intermediate 147followed by SCX-2 cartridge purification gave 10 mg of the titlecompound.

SFC Chiral Analysis (Method 14): 97.6% e.e. Rt=3.06 min.

¹H NMR (500 MHz, Methanol-d4): δ [ppm] 9.02 (s, 2H), 7.96 (s, 1H),7.69-7.63 (m, 1H), 7.57 (d, J=1.1 Hz, 1H), 7.55-7.50 (m, 1H), 5.34 (q,J=7.1 Hz, 1H), 4.34-4.06 (m, 2H), 3.09 (s, 1H), 2.80 (d, J=10.2 Hz, 1H),2.61-2.47 (m, 4H), 2.39 (s, 3H), 2.32 (t, J=10.1 Hz, 1H), 2.05-1.88 (m,2H), 1.83-1.66 (m, 5H).

LCMS (Analytical Method F) Rt=2.15 min, MS (ESIpos): m/z=538.4 (M+H)⁺.

In analogy to the procedure described for Example 346, the followingexamples were prepared using TFA and the corresponding N-Boc protectedamine starting materials.

Ex. Structure Name Analytical Data 358

3-[(3- fluoroazetidin- 3-yl)methoxy]- 5-(5-methyl- 1,3-thiazol-2-yl)-N-{(1R)-1- [2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide ¹HNMR (500 MHz, DMSO-d6): δ [ppm] 9.18 (d, J = 7.1 Hz, 1H), 9.13 (s, 2H),7.96 (s, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.64-7.60 (m, 2H), 5.21 (m, 1H),4.49 (d, J = 23.7 Hz, 2H), 3.71 (m, 2H), 3.60 (m 2H), 1.62 (d, J = 7.1Hz, 3H). LCMS (Analytical Method D) Rt = 3.26 min, MS (ESIpos): m/z =496 (M + H)⁺. 359

3-{[4,4- difluoropiperidin- 3- yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide, as a mixture of 2 diastereoisomers ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.84 (s, 1H), 7.51 (s, 2H),7.40-7.36 (m, 1H), 6.89 (d, J = 6.5 Hz, 1H), 5.36 (m, 1H), 4.40 (dt, J =9.2, 3.2 Hz, 1H), 4.04 (dt, J = 9.2, 4.9 Hz, 1H), 3.37 (d, J = 12.5 Hz,1H), 3.11 (d, J = 12.4 Hz, 1H), 2.95-2.87 (m, 1H), 2.84-2.75 (m, 1H),2.52 (s, 3H), 2.50-2.37 (m, 1H), 2.16-2.05 (m, 1H), 1.96-1.82 (m, 1H),1.71 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 2.26 min, MS(ESIpos): m/z = 542 (M + H)⁺.

Example 3603-{[(3R)-4-methylmorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a stirred solution of Intermediate 28CM (129 mg, 0.37 mmol),Intermediate VI (92.7 mg, 0.41 mmol) and DIPEA (128.98 μL, 0.74 mmol) inN,N-Dimethylformamide (1 mL) at RT was added HATU (211.17 mg, 0.56 mmol)and the reaction stirred at RT for 16 h. The material was dissolved inMeCN, water and DMSO and purified by preparative HPLC (Method A). Purefractions were evaporated before freeze drying to give 107 mg (54.9%yield) of the title compound as a white flocculent solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.86 (t, J=1.3 Hz,1H), 7.56 (dd, J=2.4, 1.4 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.41-7.39 (m,1H), 6.60 (d, J=6.5 Hz, 1H), 5.36 (m, 1H), 4.14-4.10 (m, 2H), 3.93 (dd,J=11.2, 3.0 Hz, 1H), 3.83 (dt, J=11.4, 2.8 Hz, 1H), 3.71 (td, J=10.9,2.5 Hz, 1H), 3.60 (dd, J=11.3, 9.4 Hz, 1H), 2.77 (dt, J=11.8, 2.5 Hz,1H), 2.61-2.55 (m, 1H), 2.54 (d, J=1.1 Hz, 3H), 2.46-2.42 (m, 1H), 2.41(s, 3H), 1.72 (d, J=7.2 Hz, 3H).

LCMS (Analytical Method F) Rt=2.09 min, MS (ESIpos): m/z=522.1 (M+H)⁺.

In analogy to the procedure described for Example 360, the followingexamples were prepared using HATU and the corresponding carboxylic acidand primary amine starting material.

Ex. Structure Name Analytical Data 361

3-{[(3S)-4- methylmorpholin- 3- yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[6- (trifluoromethyl) pyridin-3- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.81 (s, 1H),7.96-7.83 (m, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H),7.47 (s, 1H), 6.64 (s, 1H), 5.41 (m 1H), 4.29-4.07 (m, 2H), 4.00-3.93(m, 1H), 3.87 (d, J = 11.2 Hz, 1H), 3.77 (t, J = 10.5 Hz, 1H), 3.66 (t,J = 10.3 Hz, 1H), 2.84 (d, J = 10.7 Hz, 1H), 2.72-2.61 (m, 1H), 2.56 (s,3H), 2.53-2.49 (m, 1H), 2.47 (s, 3H), 1.70 (d, J = 7.0 Hz, 3H). LCMS(Analytical Method F) 2.20 min, MS (ESIpos): m/z = 521.1 (M + H)⁺. 362

3-{[(3S)-4- methylmorpholin- 3- yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyridin-5- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.86 (s, 2H), 7.79 (s,1H), 7.51-7.46 (m 1H), 7.45-7.42 (m, 1H), 7.35 (s, 1H), 6.59 (d, J = 5.8Hz, 1H), 5.28 (m 1H), 4.06 (d, J = 4.9 Hz, 2H), 3.86 (dd, J = 11.2, 3.2Hz, 1H), 3.76 (d, J = 11.4 Hz, 1H), 3.70-3.61 (m, 1H), 3.54 (dd, J =11.2, 9.6 Hz, 1H), 2.71 (d, J = 11.8 Hz, 1H), 2.54 (d, J = 4.6 Hz, 1H),2.49-2.44 (m, 3H), 2.41-2.37 (m, 1H), 2.35 (s, 3H), 1.64 (d, J = 7.2 Hz,3H). LCMS (Analytical Method F) Rt = 2.07 min, MS (ESIpos): m/z = 522.0(M + H)⁺. 363

3-{[(3R)-4- methylmorpholin- 3- yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[6- (trifluoromethyl) pyridin-3- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.77 (d, J = 1.9 Hz,1H), 7.91-7.83 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 2.4, 1.4Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 2.4, 1.5 Hz, 1H), 6.64(d, J = 7.0 Hz, 1H), 5.37 (m, 1H), 4.10 (d, J = 4.5 Hz, 2H), 3.92 (dd, J= 11.3, 2.9 Hz, 1H), 3.82 (dt, J = 11.4, 2.8 Hz, 1H), 3.70 (td, J =11.3, 10.9 2.5 Hz, 1H), 3.59 (dd, J = 11.3, 9.4 Hz, 1H), 2.75 (dt, J =11.8, 2.6 Hz, 1H), 2.56 (m, 1H), 2.52 (d, J = 1.1 Hz, 3H), 2.45-2.39 (m4H), 1.66 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 3.32 min,MS (ESIpos): 521 (M + H)⁺. 364

3-{[4-fluoro-1- methylpyrrolidin- 2- yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide, as a mixture of stereoisomers ¹H NMR (500 MHz, Chloroform-d):δ [ppm] 8.94 (s, 2H), 7.87 (s, 1H), 7.60-7.55 (m, 1H), 7.52 (d, J = 1.1Hz, 1H), 7.46 (s, 1H), 6.77 (s, 1H), 5.36 (m 1H), 5.16 (dt, J = 54.2,4.6 Hz, 1H), 4.21 (dd, J = 9.5, 5.4 Hz, 1H), 4.10 (dd, J = 9.5, 5.4 Hz,1H), 3.42 (dd, J = 17.3, 12.5 Hz, 1H), 2.82 (s, 1H), 2.60- 2.37 (m, 8H),2.09 (ddd, J = 30.6, 15.2, 6.7 Hz, 1H), 1.72 (d, J = 7.2 Hz, 3H). LCMS(Analytical Method F) Rt = 2.13 min, MS (ESIpos): m/z = 524 (M + H)⁺.365

3-{[4-fluoro-1- methylpyrrolidin- 2- yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)-N- {(1R)-1-[6- (trifluoromethyl) pyridin-3- yl]ethyl}benzamide, as a mixture of stereoisomers ¹H NMR (500 MHz, Chloroform-d):δ [ppm] 8.79 (d, J = 1.7 Hz, 1H), 7.90 (dd, J = 8.1, 1.9 Hz, 1H), 7.87(s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.58-7.55 (m 1H), 7.51 (d, J = 1.1Hz, 1H), 7.47 (s, 1H), 6.67 (s, 1H), 5.39 (m, 1H), 5.16 (dt, J = 54.0,4.3 Hz, 1H), 4.21 (dd, J = 9.3, 5.5 Hz, 1H), 4.10 (dd, J = 9.4 5.4 Hz,1H), 3.42 (dd, J = 18.1, 11.8 Hz, 1H), 2.81 (s, 1H), 2.63- 2.37 (m, 8H),2.09 (ddd, J = 30.4, 14.9, 6.6 Hz, 1H), 1.67 (d, J = 7.1 Hz, 3H). LCMS(Analytical Method F) Rt = 2.22 min, MS (ESIpos): m/z = 523 (M + H)⁺.

Example 3663-{[(2R)-4-methylmorpholin-2-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

To a solution of Intermediate 138 (82 mg, 0.16 mmol) in methanol (2 mL)was added formaldehyde (37% aqueous solution, 0.02 mL, 0.32 mmol) andacetic acid (0.009 mL, 0.16 mmol) and the reaction was stirred at RT for15 minutes. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was addedand the reaction stirred for 1.5 hours. The reaction mixture was passedthrough an SCX cartridge (washing with methanol, eluting with 7N ammoniain methanol) and concentrated under reduced pressure. The resultingresidue was triturated with water, filtered and dried in a high vacuumoven to give 37 mg (44% yield) of the title compound as beige solid.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.13 (d, J=7.3 Hz, 1H), 8.83 (s, 1H),8.12-8.05 (m, 1H), 7.94 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.65 (s, 1H),7.55 (s, 2H), 5.29 (m, 1H), 4.12 (d, J=4.9 Hz, 2H), 3.83 (d, J=10.4 Hz,2H), 3.64-3.45 (m, 1H), 2.80 (d, J=11.0 Hz, 1H), 2.67-2.57 (m, 1H), 2.21(s, 3H), 2.02 (td, J=11.2, 3.0 Hz, 1H), 1.94 (t, J=10.6 Hz, 1H), 1.57(d, J=7.1 Hz, 3H).

LCMS (Analytical Method F) Rt=2.18 min, MS (ESIpos): m/z=521.2 (M+H)⁺.

In analogy to the procedure described for Example 366, the followingexamples were prepared using STAB and the corresponding amine andaldehyde or ketone starting materials.

Ex. Structure Name Analytical Data 367

3-(5-chloro- 1,3-thiazol-2- yl)-5-{[(2R)-4- methylmorpholin-2-yl]methoxy}-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H),7.82 (s, 1H), 7.67 (s, 1H), 7.59-7.51 (m, 1H), 7.43 (s, 1H), 6.62 (s,1H). 5.36 (m, 1H), 4.13 (dd, J = 9.8, 5.9 Hz, 1H), 4.09-3.99 (m, 2H),3.99-3.93 (m, 1H), 3.79 (t, J = 11.0 Hz, 1H), 2.88 (d, J = 10.2 Hz, 1H),2.73 (d, J = 11.4 Hz, 1H), 2.37 (s, 3H), 2.25 (t, J = 10.5 Hz, 1H), 2.11(t, J = 9.5 Hz, 1H), 1.72 (d, J = 7.1 Hz, 3H). LCMS (Analytical MethodF) Rt = 2.28 min, MS (ESIpos): m/z = 542.0 (M + H)⁺. 368

3-{[(2S)-4- methylmorpholin- 2-yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)- N-{[2- (trifluoromethyl) pyrimidin-5-yl] methyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.86 (s, 2H), 7.80 (t,J = 1.3 Hz, 1H), 7.50 (dd, J = 2.3, 1.5 Hz, 1H), 7.42 (d, J = 1.1 Hz,1H), 7.37-7.32 (m, 1H), 6.95 (t, J = 5.8 Hz, 1H), 4.65 (d, J = 6.0 Hz,2H), 4.05 (dd, J = 9.9, 5.9 Hz, 1H), 3.98 (dd, J = 9.9, 4.2 Hz, 1H),3.96- 3.85 (m, 2H), 3.70 (td, J = 11.4, 2.4 Hz, 1H), 2.80 (d, J = 11.2Hz, 1H), 2.64 (d, J = 11.5 Hz, 1H), 2.45 (d, J = 1.0 Hz, 3H), 2.29 (s,3H), 2.16 (td, J = 11.4, 3.3 Hz, 1H), 2.02 (t, J = 10.7 Hz, 1H). LCMS(Analytical Method F) Rt = 1.99 min, MS (ESIpos): m/z = 508 (M + H)⁺.369

N-{(1R)-1-[6- (difluoromethyl) pyridin-3- yl]ethyl}-3- {[(2R)-4-methylmorpholin- 2-yl]methoxy}-5- (5-methyl-1,3- thiazol-2- yl)benzamide¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.73-8.65 (m, 1H), 7.87- 7.83(m, 2H), 7.62 (d, J = 8.1 Hz, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.41 (s,1H), 6.75-6.51 (m, 2H), 5.37 (m, 1H), 4.17-3.94 (m, 4H), 3.89- 3.75 (m1H), 2.97-2.85 (m, 1H), 2.83-2.71 (m, 1H), 2.52 (s, 3H), 2.47-2.33 (m,3H), 2.34-2.25 (m, 1H), 2.22-2.11 (m, 1H), 1.66 (d, J = 7.1 Hz, 3H).LCMS (Analytical Method F) Rt = 2.01 min, MS (ESIpos): m/z = 503.1 (M +H)⁺. 370

3-{[(2S)-4- methylmorpholin 2-yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)- N-{(1R)-1-[6- (trifluoromethyl) pyridin-3- yl]ethyl}benzamide ¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.13 (d, J = 7.3 Hz, 1H),8.83 (d, J = 1.5 Hz, 1H), 8.09 (dd, J = 8.2, 1.7 Hz, 1H), 7.94 (s, 1H),7.90 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 1.1 Hz, 1H), 7.55 (s, 2H), 5.29(m, 1H), 4.12 (d, J = 5.0 Hz, 2H), 3.88-3.74 (m, 2H), 3.56 (td, J =11.2, 2.4 Hz, 1H), 2.80 (d, J = 11.1 Hz, 1H), 2.68-2.60 (m, 1H), 2.21(s, 3H), 2.02 (td, J = 11.3, 3.2 Hz, 1H), 1.93 (t, J = 10.6 Hz, 1H),1.57 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 2.21 min, MS(ESIpos): m/z = 521.1 (M + H)⁺. 371

3-[(3-fluoro-1- methylazetidin-3- yl}methoxy]-5- (5-methyl-1,3-thiazol-2-yl)- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.89 (t,J = 1.3 Hz, 1H), 7.59 (dd, J = 2.4, 1.4 Hz, 1H), 7.52 (d, J = 1.2 Hz,1H), 7.46-7.43 (m, 1H), 6.69 (d, J = 6.6 Hz, 1H), 5.37 (m, 1H), 4.38 (d,J = 22.9 Hz, 2H), 3.73-3.61 (m, 2H), 3.30-3.15 (m, 2H), 2.53 (d, J = 1.1Hz, 3H), 2.45 (s, 3H), 1.72 (d, J = 7.2 Hz, 3H). LCMS (Analytical MethodF) Rt = 3.44 min, MS (ESIpos): m/z = 510.0 (M + H)⁺. 372

3-{[(2R)-4- methylmorpholin- 2-yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)- N-{[2- (trifluoromethyl) pyrimidin-5-yl] methyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.86 (t,J = 1.4 Hz, 1H), 7.57 (dd, J = 2.3, 1.5 Hz, 1H), 7.50 (d, J = 1.2 Hz,1H), 7.43 (dd, J = 2.3, 1.6 Hz, 1H), 6.88 (t, J = 5.8 Hz, 1H), 4.72 (d,J = 6.0 Hz, 2H), 4.12 (dd, J = 9.9, 6.0 Hz, 1H), 4.05 (dd, J = 9.9, 4.2Hz, 1H), 4.01-3.93 (m, 2H), 3.75 (td, J = 11.4, 2.4 Hz, 1H). 2.83 (d, J= 11.2 Hz, 1H), 2.68 (d, J = 10.0 Hz, 1H), 2.52 (d, J = 1.0 Hz, 3H),2.33 (s, 3H), 2.19 (td, J = 11.4, 3.3 Hz, 1H), 2.09-2.02 (m, 1H). LCMS(Analytical Method F) Rt = 2.00 min, MS (ESIpos): m/z = 508.0 (M + H)⁺.373

3-{[(2R)-4- methylmorpholin- 2-yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)- N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.93 (t, J = 1.4 Hz,1H), 7.84 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.62 (dd, J =2.3, 1.5 Hz, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.49- 7.42 (m, 2H), 5.62 (m,1H), 4.15 (ddd, J = 8.6, 5.9, 2.7 Hz, 1H), 4.08 (dt, J = 9.8, 4.7 Hz,1H), 4.03- 3.94 (m, 2H), 3.78 (td, J = 11.4, 2.4 Hz, 1H), 2.86 (d, J =11.1 Hz, 1H), 2.70 (d, J = 11.4 Hz, 1H), 2.55 (d, J = 1.1 Hz, 3H), 2.36(s, 3H), 2.22 (td, J = 11.5, 3.3 Hz, 1H), 2.08 (td, J = 10.8, 3.8 Hz,1H), 1.78 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method F) Rt = 2.07 min,MS (ESIpos): m/z = 522 (M + H)⁺. 374

3-{[(2S)-4- methylmorpholin- 2-yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)- N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.90 (s, 1H), 7.82 (d,J = 8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.62-7.58 (m, 1H), 7.53-7.49(m, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.44- 7.40 (m, 1H), 5.60 (m, 1H),4.17- 4.10 (m, 1H), 4.09-4.04 (m, 1H), 4.04-3.99 (m, 1H), 3.97 (d, J =11.5 Hz, 1H), 13.80 (t, J = 11.1 Hz, 1H), 2.88 (d, J = 11.1 Hz, 1H),2.73 (d, J = 11.0 Hz, 1H), 2.52 (s, 3H), 2.37 (s, 3H), 2.30-2.20 (m,1H), 2.18-2.06 (m, 1H), 1.76 (d, J = 7.0 Hz, 3H). LCMS (AnalyticalMethod F) Rt = 2.10 min, MS (ESIpos): m/z = 522 (M + H)⁺. 375

3-(5-ethyl-1,3- thiazol-2-yl)-5- {[(2S)-4- methylmorpholin- 2-yl]methoxy}-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.14 (d, J = 7.1 Hz, 1H),9.12 (s, 2H), 7.94 (t, J = 1.3 Hz, 1H), 7.68 (s, 1H), 7.61-7.50 (m, 2H),5.30 (m, 1H), 4.11 (d, J = 5.0 Hz, 2H), 3.88-3.74 (m, 2H), 3.55 (td, J =11.2, 2.4 Hz, 1H), 2.90 (q, J = 7.5 Hz, 2H), 2.83-2.76 (m, 1H),2.63-2.58 (m 1H), 2.20 (s, 3H), 2.01 (td, J = 11.3, 3.2 Hz, 1H), 1.93(t, J = 10.6 Hz, 1H), 1.61 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 7.5 Hz,3H). LCMS (Analytical Method F) Rt = 2.28 min, MS (ESIpos): m/z = 536.1(M + H)⁺. 376

3-(5-chloro- 1,3-thiazol-2- yl)-5-{[(2S)-4- methylmorpholin-2-yl]methoxy}-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.82 (s,1H), 7.67 (s, 1H), 7.60-7.52 (m 1H), 7.44 (s, 1H), 6.62 (s, 1H), 5.36(m, 1H), 4.18-4.06 (m, 2H), 4.06- 4.00 (m, 1H), 3.97 (d, J = 11.6 Hz,1H), 3.80 (t, J = 10.6 Hz, 1H), 2.89 (d, J = 10.4 Hz, 1H), 2.74 (d, J =10.6 Hz, 1H), 2.38 (s, 3H), 2.33- 2.19 (m, 1H), 2.19-2.09 (m, 1H), 1.73(d, J = 7.1 Hz, 3H). LCMS (Analytical Method F) Rt = 2.00 min, MS(ESIpos): m/z = 542.0 (M + H)⁺. 377

3-(5-ethyl-1,3- thiazol-2-yl)-5- {[(2R)-4- methylmorpholin-2-yl]methoxy}-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz, DMSO-d6): δ [ppm] 9.20-9.06 (m, 3H), 7.94 (t,J = 1.3 Hz, 1H), 7.68 (s, 1H), 7.55 (dt, J = 8.2, 2.3 Hz, 2H), 5.30 (m,1H), 4.18-4.06 (m, 2H), 3.89- 3.73 (m, 2H), 3.55 (td, J = 11.2, 2.4 Hz,1H), 2.90 (q, J = 7.5 Hz, 2H), 2.83-2.74 (m, 1H), 2.70- 2.56 (m, 1H),2.20 (s, 3H), 2.01 (td, J = 11.3, 3.3 Hz, 1H), 1.93 (t, J = 10.6 Hz,1H), 1.61 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 7.5 Hz, 3H). LCMS(Analytical Method F) Rt = 2.29 min, MS (ESIpos): m/z = 536.1 (M + H)⁺.378

3-{[(2S)-1- methylpyrrolidin- 2-yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (250 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.83 (s,1H), 7.60-7.47 (m, 2H), 7.44-7.35 (m, 1H), 6.64 (d, J = 6.5 Hz, 1H),5.36 (m, 1H), 4.02 (m, 2H), 3.12 (t, J = 7.4 Hz, 1H), 2.74-2.58 (m, 1H),2.53 (d, J = 0.8 Hz, 3H), 2.47 (s, 3H), 2.40-2.21 (m, 1H), 2.10- 1.75(m, 4H), 1.70 (d, J = 7.2 Hz, 3H). LCMS (Analytical Method F) Rt = 3.41min, MS (ESIpos): m/z = 506 (M + H)⁺. 379

3-{[(2R)-1- methylpyrrolidin- 2-yl]methoxy}-5 (5-methyl-1,3-thiazol-2-yl)- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.92 (s, 2H), 7.82 (s,1H), 7.55-7.52 (m, 1H), 7.51-7.48 (m, 1H), 7.41-7.37 (m, 1H), 6.74 (d, J= 6.6 Hz, 1H), 5.35 (m, 1H), 4.04 (dd, J = 9.3, 5.2 Hz, 1H), 3.99 (dd, J= 9.3, 5.1 Hz, 1H), 3.15-3.08 (m, 1H), 2.69-2.60 (m, 1H), 2.54- 2.50 (m,3H), 2.47 (s, 3H), 2.34- 2.25 (m, 1H), 2.07-1.97 (m, 1H), 1.90-1.71 (m,3H), 1.69 (d, J = 7.2 Hz, 3H). LCMS (Analytical Method F) Rt = 3.41 min,MS (ESIpos): m/z = 506 (M + H)⁺. 380

3-[(1- methylpiperidin- 4-yl)methoxy]-5- (5-methyl-1,3- thiazol-2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 8.95 (s, 2H), 7.83 (t, J = 1.4 Hz, 1H),7.52 (dt, J = 4.6, 1.3 Hz, 2H), 7.42-7.36 (m, 1H), 6.74 (s, 1H), 5.36(m, 1H), 3.93 (d, J = 5.8 Hz, 2H), 2.98 (d, J = 10.8 Hz, 2H), 2.53 (d, J= 1.1 Hz, 3H), 2.36 (s, 3H), 2.08 (t, J = 11.3 Hz, 2H), 1.90- 1.80 (m,3H), 1.72 (d, J = 7.2 Hz, 3H), 1.63-1.49 (m, 2H). LCMS (AnalyticalMethod F) Rt = 2.23 min, MS (ESIpos): m/z = 520 (M + H)⁺. 381

3-(5-methyl- 1,3-thiazol-2- yl)-5-{[(2R)-4- (propan-2- yl)morpholin-2-yl]methoxy}- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.96 (s, 2H), 7.89 (s,1H), 7.60 (s, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.41 (s, 1H), 5.38 (m, 1H),4.14 (s, 1H), 4.11-4.05 (m, 1H), 4.05-3.70 (m, 3H), 2.85 (s, 4H), 2.53(d, J = 1.1 Hz, 3H), 1.73 (d, J = 7.1 Hz, 3H), 1.43-0.99 (m, 7H). LCMS(Analytical Method F) Rt = 3.40 min, MS (ESIpos): m/z = 550 (M + H)⁺.382

3-(5-methyl- 1,3-thiazol-2- yl)-5-{[(2R)-4- (propan-2- yl)morpholin-2-yl]methoxy}- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide ¹H NMR (500 MHz, DMSO-d6): δ [ppm] 1.00 (d, J = 6.5, 6H), 1.62(d, J = 7.1, 3H), 2.14 (t, J = 10.6, 1H), 2.19-2.29 (m, 1H), 2.53 (s,3H) 2.58-2.68 (m, 2H), 2.79-2.88 (m, 1H), 3.47-3.59 (m, 1H), 3.75- 3.82(m, 1H), 3.82-3.88 (m, 1H), 4.06-4.17 (m, 2H), 5.26-5.35 (m, 1H), 7.56(s, 2H), 7.65 (d, J = 1.2, 1H), 7.93 (s, 1H), 9.12 (s, 2H), 9.15 (d, J =7.1, 1H), LCMS (Analytical Method F) Rt = 2.23 min, MS (ESIpos): m/z =550 (M + H⁾⁺. 383

3-{[4,4- difluoro-1- methylpiperidin- 3-yl]methoxy}-5- (5-methyl-1,3-thiazol-2-yl)- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide, as a mixture of 2 diastereoisomers ¹H NMR (500 MHz,Chloroform-d): δ [ppm] 8.87 (s, 2H), 7.80-7.76 (m, 1H), 7.48-7.43 (m,2H), 7.32 (s, 1H), 6.63 (d, J = 6.5 Hz, 1H), 5.30 (m, 1H), 4.32 (dt, J =9.1, 3.2 Hz, 1H), 4.02-3.94 (m, 1H), 2.95 (d, J = 9.3 Hz, 1H), 2.71-2.65(m, 1H), 2.56-2.48 (m, 1H), 2.46 (d, J = 0.6 Hz, 3H), 2.33-2.24 (m, 4H),2.19 (t, J = 9.9 Hz, 1H), 2.06-1.94 (m, 2H), 1.65 (d, J = 7.1 Hz, 3H).LCMS (Analytical Method F) Rt = 2.29 min, MS (ESIpos): m/z = 556 (M +H)⁺.

Example 383 was formed as a mixture of two diastereoisomers. SFC ChiralPurification (Method 15) provided diastereoisomer 1 (Example 384) anddiastereoisomer 2 (Example 385).

Example 384 Diastereoisomer 1;3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral Purification (Method 15) on 90.3 mg of Example 383 gave 32.9mg of the title compound as white solid.

SFC Chiral Analysis (Method 15): 99.2% e.e. Rt=1.71 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.84 (t, J=1.4 Hz,1H), 7.54 (dd, J=2.4, 1.4 Hz, 1H), 7.54-7.52 (m, 1H), 7.39 (dd, J=2.3,1.6 Hz, 1H), 6.58 (d, J=6.4 Hz, 1H), 5.37 (m, 1H), 4.39 (dd, J=9.4, 3.8Hz, 1H), 4.06 (t, J=9.2 Hz, 1H), 3.03 (d, J=10.4 Hz, 1H), 2.79-2.72 (m,1H), 2.65-2.56 (m, 1H), 2.54 (d, J=1.1 Hz, 3H), 2.41-2.31 (m, 4H),2.31-2.20 (m, 1H), 2.14-2.00 (m, 2H), 1.72 (d, J=7.2 Hz, 3H).

LC-MS (Analytical Method F) Rt=2.32 min, MS (ESIpos): m/z=556 (M+H)⁺.

Example 385 Diastereoisomer 2;3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

SFC Chiral Purification (Method 15) on 90.3 mg of Example 383 gave 27 mgof the title compound.

SFC Chiral Analysis (Method 15): 99.9% e.e. Rt=2.06 min.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.84 (t, J=1.4 Hz,1H), 7.55 (dd, J=2.4, 1.4 Hz, 1H), 7.53 (d, J=1.2 Hz, 1H), 7.39 (dd,J=2.3, 1.6 Hz, 1H), 6.57 (d, J=6.5 Hz, 1H), 5.37 (m, 1H), 4.40 (dd,J=9.4, 3.8 Hz, 1H), 4.06 (t, J=9.2 Hz, 1H), 3.02 (d, J=10.4 Hz, 1H),2.75 (d, J=11.2 Hz, 1H), 2.65-2.55 (m, 1H), 2.54 (d, J=1.1 Hz, 3H),2.39-2.31 (m, 4H), 2.26 (t, J=10.1 Hz, 1H), 2.07 (m, 2H), 1.72 (d, J=7.2Hz, 3H).

LC-MS (Analytical Method F) Rt=2.32 min, MS (ESIpos): m/z=556 (M+H)⁺.

In analogy to the procedure described for Example 346, the followingexamples were prepared using T3P and the corresponding carboxylic acidand primary amine starting materials.

Ex. Structure Name Analytical Data 386

3-[(3-fluoro-1- methylazetidin-3- yl)methoxy]-5-(5- methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6- (trifluoromethyl) pyridin-3-yl] ethyl}benzamide ¹HNMR (500 MHz, Chloroform-d): δ [ppm] 8.79 (d, J = 1.7 Hz, 1H), 7.93-7.85(m, 2H), 7.67 (d, J = 8.1 Hz, 1H), 7.59 (dd, J = 2.3, 1.5 Hz, 1H), 7.52(d, J = 1.1 Hz, 1H), 7.47-7.44 (m, 1H), 6.62 (d, J = 7.0 Hz, 1H), 5.39(m, 1H), 4.38 (d, J = 22.7 Hz, 2H), 3.74- 3.58 (m, 2H), 3.25 (dd, J =21.7, 9.5 Hz, 2H), 2.53 (d, J = 1.0 Hz, 3H), 2.46 (s, 3H), 1.67 (d, J =7.1 Hz, 3H). LCMS (Method A) Rt = 3.49 min, MS (ESIpos): m/z = 509.05(M + H)⁺. 387

3-(5-ethyl-1,3- thiazol-2-yl)-5-[(3- fluoro-1- methylazetidin-3-yl)methoxy]-N- {(1R)-1-[6- (trifluoromethyl) pyridin-3-yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.81 (s, 1H),7.95-7.88 (m, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.62 (s, 1H), 7.57 (s, 1H),7.52 (s, 1H), 6.74 (s, 1H), 5.41 (m, 1H), 4.50-4.31 (m, 2H), 3.75 (t, J= 9.7 Hz, 2H), 3.30 (dd, J = 21.5, 8.7 Hz, 2H), 2.93 (q, J = 7.6 Hz,2H), 2.50 (s, 3H), 1.70 (d, J = 7.1 Hz, 3H), 1.39 (t, J = 7.5 Hz, 3H).LCMS (Analytical Method F) Rt = 2.39 min, MS (ESIpos): m/z = 523 (M +H)⁺. 388

3-{[(3R)-4- methylmorpholin-3- yl]methoxy}-5-(5- methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl] ethyl}benzamide ¹HNMR (500 MHz, Chloroform-d): δ [ppm] 7.90 (s, 1H), 7.82 (d, J = 8.7 Hz,1H), 7.74 (d, J = 8.7 Hz, 1H), 7.61-7.59 (m, 1H), 7.52 (d, 1H),7.49-7.45 (m, 1H), 7.44 (s, 1H), 5.61 (m, 1H), 4.21-4.15 (m, 1H), 4.12(dd, J = 9.8, 5.2 Hz, 1H), 3.95 (dd, J = 11.4, 2.7 Hz, 1H), 3.88-3.83(m, 1H), 3.80-3.72 (m, 1H), 3.64 (t, J = 10.0 Hz, 1H), 2.81 (d, J = 10.8Hz, 1H), 2.66 (s, 1H), 2.53 (s, 3H), 2.46 (m, 4H), 1.76 (d, J = 7.0 Hz,3H). LCMS (Analytical Method F) Rt = 2.04 min, MS (ESIpos): m/z = 522(M + H)⁺. 389

3-{[(3S)-4- methylmorpholin-3- yl]methoxy}-5-(5- methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl] ethyl}benzamide ¹HNMR (500 MHz, Chloroform-d): δ [ppm] 7.90 (s, 1H), 7.82 (d, J = 8.7 Hz,1H), 7.74 (d, J = 8.7 Hz, 1H), 7.62-7.58 (m, 1H), 7.52 (d, J = 1.0 Hz,1H), 7.49-7.45 (m, 1H), 7.45-7.43 (m, 1H), 5.61 (m, 1H), 4.22-4.15 (m,1H), 4.15-4.09 (m, 1H), 3.95 (dd, J = 11.3, 2.9 Hz, 1H), 3.88-3.82 (m,1H), 3.80-3.72 (m, 1H), 3.64 (t, J = 10.3 Hz, 1H), 2.81 (d, J = 9.9 Hz,1H), 2.66 (s, 1H), 2.53 (d, 3H), 2.46 (m, 4H), 1.76 (d, J = 7.0 Hz, 3H).LCMS (Analytical Method F) Rt = 2.03 min, MS (ESIpos): m/z = 522 (M +H)⁺.

Example 3903-{[(2R)-4-ethylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A solution of Example 347 (80 mg, 0.15 mmol), iodoethane (14.5 μL, 0.18mmol) and potassium carbonate (31 mg, 0.23 mmol) in acetonitrile (2 mL)was stirred for 1 h at RT. The reaction mixture was then heated to 80°C. by microwave irradiation for 20 mins. The reaction was re-treatedwith iodoethane (14.5 μL, 0.18 mmol) and heated to 80° C. by microwaveirradiation for a further 20 mins. The reaction mixture was filteredthrough Celite® and concentrated under reduced pressure.

The crude material was purified by preparative HPLC (Method A) andfreeze-dried from MeCN/water to afford 40.4 mg (50% yield) of the titlecompound as white powder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87 (t, J=1.4 Hz,1H), 7.57 (dd, J=2.4, 1.5 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.41 (dd,J=2.3, 1.6 Hz, 1H), 6.63 (d, J=6.5 Hz, 1H), 5.36 (m, 1H), 4.12 (dd,J=9.9, 6.0 Hz, 1H), 4.05 (dd, J=9.9, 4.1 Hz, 1H), 4.01-3.94 (m, 2H),3.76 (td, J=11.4, 2.4 Hz, 1H), 2.91 (d, J=11.1 Hz, 1H), 2.77 (d, J=11.5Hz, 1H), 2.53 (d, J=1.1 Hz, 3H), 2.46 (q, J=7.2 Hz, 2H), 2.17 (td,J=11.4, 3.3 Hz, 1H), 2.03 (t, J=10.7 Hz, 1H), 1.71 (d, J=7.2 Hz, 3H),1.11 (t, J=7.2 Hz, 3H).

LCMS (Analytical Method F) Rt=2.17 min, MS (ESIpos): m/z=536 (M+H)⁺.

Example 3913-{[(2R)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A stirred mixture of Example 347 (100 mg, 0.19 mmol),1,1-difluoro-2-iodoethane (20 μL, 0.21 mmol) and potassium carbonate (40mg, 0.29 mmol) in anhydrous acetonitrile (3 mL) was heated to 80° C. bymicrowave irradiation for 20 mins. Additional 1,1-difluoro-2-iodoethane(40 μL, 0.42 mmol) and potassium carbonate (40 mg, 0.29 mmol) was addedand the reaction mixture heated to 100° C. by microwave irradiation for20 mins. A further quantity of 1,1-difluoro-2-iodoethane (100 μL, 2.1mmol) was added and the reaction mixture heated to 100° C. for 3 h bymicrowave irradiation. Further 1,1-difluoro-2-iodoethane (100 μL, 2.1mmol) was added and the reaction mixture heated to 100° C. for 2 h bymicrowave irradiation. The reaction mixture was filtered, concentratedunder reduced pressure and purified by preparative HPLC (Method B) thenlyophilised from acetonitrile/water to give 64 mg (58% yield) of thetitle compound as white solid.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87 (s, 1H), 7.56(dd, J=2.3, 1.4 Hz, 1H), 7.52 (d, J=1.1 Hz, 1H), 7.43-7.35 (m, 1H), 6.62(d, J=6.3 Hz, 1H), 5.92 (t, J=55.9 Hz, 1H), 5.36 (m, 1H), 4.11 (dd,J=9.8, 5.7 Hz, 1H), 4.04 (dd, J=9.8, 4.4 Hz, 1H), 4.01-3.96 (m, 1H),3.96-3.92 (m, 1H), 3.81-3.72 (m, 1H), 2.94 (d, J=11.1 Hz, 1H), 2.84-2.74(m, 3H), 2.53 (d, J=0.9 Hz, 3H), 2.48 (td, J=11.3, 2.7 Hz, 1H), 2.35 (t,J=10.6 Hz, 1H), 1.71 (d, J=7.2 Hz, 3H).

LC-MS (Analytical Method F) Rt=3.24 min, MS (ESIpos): m/z=572 (M+H)⁺.

Example 392 Methyl(2R)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate

To a solution of Example 347 (35 mg, 69.0 μmol) in DCM (1 mL) was addedDIPEA (24 μL, 138 μmol) and methyl chloroformate (8.0 μL, 103 μmol) atRT. The reaction was stirred for 1 h then diluted with DCM (3 mL) andwashed with saturated NaHCO₃ (3 mL). The aqueous layer was extractedwith DCM (2×3 mL). The combined DCM layers were dried (MgSO₄), filteredand concentrated under reduced pressure. The crude material was purifiedby Biotage Isolera™ chromatography (eluting with 0-20% MeOH in DCM on a10 g pre-packed KP-SiO₂ column) and the product freeze-dried fromMeCN/water to give 31.8 mg (82% yield) of the title compound as whitepowder.

¹H NMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.88 (s, 1H), 7.57(dd, J=2.4, 1.4 Hz, 1H), 7.53 (d, J=1.1 Hz, 1H), 7.42-7.39 (m, 1H), 6.64(d, J=5.8 Hz, 1H), 5.36 (m, 1H), 4.21-4.09 (m, 2H), 4.07 (dd, J=9.9, 4.7Hz, 1H), 4.02-3.87 (m, 2H), 3.86-3.78 (m, 1H), 3.74 (s, 3H), 3.61 (t,J=11.6 Hz, 1H), 3.07 (s, 1H), 2.93 (s, 1H), 2.54 (d, J=1.1 Hz, 3H), 1.72(d, J=7.2 Hz, 3H).

LCMS (Analytical Method D) Rt=4.31 min, MS (ESIpos): m/z=566 (M+H)⁺.

In analogy to the procedure described for Example 392, the followingexample was prepared from the corresponding secondary amine andchloroformate starting materials.

Ex. Structure Name Analytical Data 393

Methyl (2S)-2- {[3-(5-methyl- 1,3-thiazol-2- yl)-5-({(1R)-1- [2-(trifluoromethyl) pyrimidin-5-yl] ethyl}carbamoyl) phenoxy]methyl}morpholine-4- carboxylate ¹H NMR (500 MHz, DMSO-d6): δ [ppm] 1.61 (d, J= 7.1, 3H), 2.52 (s, 3H), 2.79-3.08 (m, 2H), 3.49 (td, J = 11.6, 2.8,1H), 3.63 (s, 3H), 3.73- 3.83 (m, 2H), 3.88 (d, J = 11.2, 1H), 3.94-4.05(m, 1H), 4.11- 4.22 (m, 2H), 5.25-5.35 (m, 1H), 7.52-7.59 (m, 2H), 7.64(d, J = 1.2, 1H), 7.93 (t, J = 1.3, 1H), 9.12 (s, 2H), 9.15 (d, J = 7.1,1H). LCMS (Analytical Method F) Rt = 3.38 min, MS (ESIpos): m/z = 566(M + H)⁺.

Example 3943-(Azetidin-3-ylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A mixture of Intermediate 148 (90.0 mg, 156 μmol), TFA (60 μL, 780 μmol)in DCM was stirred at RT for 18 h. The mixture was evaporated to drynessand the residue purified by preparative HPLC (method 1, LCMS, Rt: 0.85min) to give 15.0 mg (18% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 3.10-3.21 (m, 1 H)3.63-3.78 (m, 2 H) 3.93 (s, 2 H) 4.27 (d, 2 H) 5.19-5.39 (m, 1 H)7.49-7.70 (m, 3 H) 7.88-7.99 (m, 1 H) 9.12 (s, 2 H) 9.20-9.33 (m, 1 H).

LCMS, method 1, rt: 0.85 min, MS ES+ m/z=478 (M+H)⁺.

Example 3953-{[(3R)-4-methyl-5-oxomorpholin-3-yl]methoxyl}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A mixture of Intermediate 5CX (417 mg, 1.15 mmol), Intermediate VI (367mg, 1.61 mmol), HATU (1.05 g, 2.76 mmol) and DIPEA (980 μL, 5.8 mmol) inDMF (52 mL) was stirred at 60° C. for 12 h. The mixture was evaporatedto dryness under reduced pressure and the residue purified by columnchromatography (silica gel, hexane/EE gradient) to give 313 mg (49%yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 3.01 (s, 3 H) 3.70-3.81(m, 1 H) 3.89 (d, 1 H) 3.96-4.12 (m, 3 H) 4.22-4.41 (m, 2 H) 5.30 (s, 1H) 7.50-7.70 (m, 3 H) 7.96 (t, 1 H) 9.06-9.27 (m, 3 H).

LCMS, method 1, rt: 1.15 min, MS ES+ m/z=536 (M+H)⁺.

In analogy to the synthesis procedure described for Example 395, thefollowing examples were prepared from the respective starting materials:

Ex. Structure Name Analytical Data 396

3-(5-methyl-1,3- thiazol-2-yl)-5- {[(3R)-5- oxomorpholin-3-yl]methoxy}-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS, method 1, rt: 1.06 min, MS ES+ m/z = 522 (M + H)⁺;¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 3.70-3.80 (m, 1 H) 3.86(t, 2 H) 3.97-4.12 (m, 3 H) 4.17 (d, 1 H) 5.30 (s, 1 H) 7.50-7.70 (m, 3H) 7.91-8.01 (m, 1 H) 8.30 (d, 1 H) 9.12 (s, 2 H) 9.20 (d, 1 H) 397

3-{[(5S)-3-methyl-2- oxo-1,3-oxazolidin- 5-yl]methoxy}-5-(5-methyl-1,3-thiazol- 2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS, method 1, rt: 1.11 min, MS ES+ m/z = 522 (M +H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 2.79 (s, 3 H) 3.43(dd, 1 H) 3.70 (t, 1 H) 4.18-4.41 (m, 2 H) 4.79-4.97 (m, 1 H) 5.30 (s, 1H) 7.52-7.71 (m, 3 H) 7.95 (t, 1 H) 9.12 (s, 2 H) 9.20 (d, 1 H) 398

3-{[(5R)-3-methyl-2- oxo-1,3-oxazolidin- 5-yl]methoxy}-5-(5-methyl-1,3-thiazol- 2-yl)-N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS, method 1, rt: 1.11 min, MS ES+ m/z = 522 (M +H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 2.79 (s, 3 H)3.38-3.49 (m, 1 H) 3.70 (s, 1 H) 4.19-4.40 (m, 2 H) 4.82-4.96 (m, 1 H)5.30 (s, 1 H) 7.49-7.71 (m, 3 H) 7.95 (t, 1 H) 9.12 (s, 2 H) 9.19 (d, 1H) 399

3-{[(2R)-4-methyl-5- oxomorpholin-2-yl] methoxy}-5-(5-methyl-1,3-thiazol- 2-yl)-N-{(1R)-1-[2- (trifluoromethyl)pyrimidin-5-yl] ethyl}benzamide LCMS, method 1, rt: 1.09 min, MS ES+ m/z= 536 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 2.89(s, 3 H) 3.35-3.39 (m, 1 H) 3.42-3.54 (m, 1 H) 4.13 (s, 2 H) 4.23 (s, 3H) 5.21- 5.37 (m, 1 H) 7.50-7.69 (m, 3 H) 7.88-7.99 (m, 1H) 9.12 (s, 3H) 400

3-(5-methyl-1,3- thiazol-2-yl)-5- {[(2S)-5- oxomorpholin-2-yl]methoxy}-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS, method 1, rt: 1.04 min, MS ES+ m/z = 522 (M +H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.60 (d, 3 H) 3.31 (s, 2 H) 4.09(s, 3 H) 4.15-4.28 (m, 2 H) 5.21-5.37 (m, 1 H) 7.50- 7.68 (m, 3 H) 7.94(s, 1 H) 8.02-8.13 (m, 1 H) 9.12 (s, 3 H) 401

3-{[(2S)-4-methyl-5- oxomorpholin-2-yl] methoxy}-5-(5-methyl-1,3-thiazol- 2-yl)-N-{(1R)-1-[2- (trifluoromethyl)pyrimidin-5-yl] ethyl}benzamide LCMS, method 1, rt: 1.09 min, MS ES+ m/z= 536 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 2.89(s, 3 H) 3.35- 3.41 (m, 1 H) 3.48 (s, 1 H) 4.13 (s, 2 H) 4.18-4.31 (m, 3H) 5.30 (s, 1 H) 7.54- 7.61 (m, 2 H) 7.65 (d, 1 H) 7.94 (t, 1 H)9.06-9.25 (m, 3 H) 402

3-{[(3S)-4-methyl-5- oxomorpholin-3-yl] methoxy}-5-(5-methyl-1,3-thiazol- 2-yl)-N-{(1R)-1-[2- (trifluoromethyl)pyrimidin-5-yl] ethyl}benzamide LCMS, method 1, rt: 1.11 min, MS ES+ m/z= 536 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 3.00(s, 3 H) 3.70- 3.81 (m, 1 H) 3.88 (s, 1 H) 3.97-4.12 (m, 3 H) 4.29 (d, 2H) 5.30 (s, 1 H) 7.51- 7.69 (m, 3 H) 7.96 (t, 1 H) 9.12 (s, 2 H) 9.19(d, 1 H) 403

3-(5-methyl-1,3- thiazol-2-yl)-5- {[(3S)-5- oxomorpholin-3-yl]methoxy}-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide LCMS, method 1, rt: 1.06 min, MS ES+ m/z = 522 (M +H)⁺; ¹H NMR (500 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 3.71-3.79 (m, 1 H)3.86 (t, 2 H) 4.02 (s, 2 H) 4.08 (d, 1 H) 4.14-4.24 (m, 1 H) 5.30 (s, 1H) 7.51- 7.70 (m, 3 H) 7.95 (t, 1 H) 8.30 (d, 1 H) 9.12 (s, 2 H) 9.20(d, 1 H) 404

tert-butyl 1-{[3-(5- methyl-1,3-thiazol- 2-yl)-5-({(1R)-1-[2-(trifluoromethyl) pyrimidin-5- yl]ethyl}carbamoyl) phenoxy]methyl}-2-oxa-5- azabicyclo[2.2.1] heptane-5- carboxylate, as a mixture of 2diastereoisomers LCMS, method 1, rt: 1.37 min, MS ES+ m/z = 620 (M +H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.41 (d, 9 H) 1.61 (d, 3 H)1.84- 2.00 (m, 2 H) 3.34-3.48 (m, 2 H) 3.72-3.79 (m, 1 H) 3.81-3.91 (m,1 H) 4.44 (br. s., 3 H) 5.21-5.37 (m, 1 H) 7.52-7.72 (m, 3 H) 7.94 (t, 1H) 9.12 (s, 3 H) 405

3-[(5-isopropyl-2- oxa-5-azabicyclo [2.2.1]hept-1-yl) methoxy]-5-(5-methyl-1,3- thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl)pyrimidin-5- yl]ethyl}benzamide, as a mixture of 2 diastereoisomersLCMS, method 1, rt: 0.94 min, MS ES+ m/z = 562 (M + H)⁺; ¹H NMR (400MHz, DMSO-d₆): δ [ppm] 1.00 (t, 6 H) 1.61 (d, 3 H) 1.69- 1.86 (m, 2 H)2.61-2.76 (m, 1 H) 3.13 (d, J1 H) 3.60-3.72 (m, 2 H) 3.99 (d, 1 H)4.27-4.46 (m, 2 H) 5.30 (s, 1 H) 7.50-7.69 (m, 3 H) 7.92 (t, 1 H) 9.07-9.23 (m, 3 H) 406

3-[(5-methyl-2- oxa-5-azabicyclo [2.2.1]hept-1-yl) methoxy]-5-(5-methyl-1,3- thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl)pyrimidin-5- yl]ethyl}benzamide, as a mixture of 2 diastereoisomersLCMS, method 1, rt: 0.89 min, MS ES+ m/z = 534 (M + H)⁺; ¹H NMR (400MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 1.74 (d, 1 H) 1.90 (s, 1 H) 2.38(s, 3 H) 2.59 (s, 1 H) 2.97 (d, 1 H) 3.46 (s, 2 H) 3.67 (dd, 1 H) 4.01(d, 1 H) 4.28-4.49 (m, 2 H) 5.30 (s, 1 H) 7.50-7.71 (m, 3 H) 7.93 (s, 1H) 9.06- 9.24 (m, 1 H)

Example 4073-(5-Methyl-1,3-thiazol-2-yl)-5-[2-oxa-5-azabicyclo[2.2.1]hept-1-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide,as a Mixture of 2 Diastereoisomers

A mixture of Example 404 (610 mg, 984 μmol), TFA (5.0 mL, 65 mmol) inDCM (50 mL) was stirred at until complete conversion. The mixture wasevaporated to dryness under reduced pressure. Water, saturated aqueousNaHCO₃ and DCM were added and the phases separated. The aqueous layerwas extracted twice with DCM. The combined organic layers wereevaporated to dryness and purified by preparative HPLC (method 1, LCMS,Rt: 0.90 min) to give 480.0 mg (94% yield) of the title compound.

¹H NMR (500 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 1.67-1.80 (m, 2 H)2.92-3.03 (m, 2 H) 3.62-3.84 (m, 3 H) 4.36-4.53 (m, 2 H) 5.30 (t, 1 H)7.52-7.67 (m, 3 H) 7.93 (t, 1 H) 9.08-9.24 (m, 3 H).

LCMS, method 1, rt: 0.88 min, MS ES+ m/z=520 (M+H)⁺.

In analogy to the synthesis procedure described for Example 366, thefollowing examples were prepared using STAB and the corresponding amineand aldehyde or ketone starting materials and purified by preparativeHPLC (method 1):

Ex. Structure Name Analytic 408

3-(5-methyl-1,3- thiazol-2-yl)-5-[(5- propyl-2- oxa-5-azabicyclo[2.2.1]hept-1-yl) methoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5-yl]ethyl}benzamide, as a mixture of 2 diastereoisomers LCMS, method 1,rt: 0.93 min, MS ES+ m/z = 562 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ[ppm] 0.88 (t, 3 H) 1.32-1.47 (m, 2 H) 1.61 (d, 3 H) 1.68-1.75 (m, 1 H)1.80-1.89 (m, 1 H) 2.96-3.04 (m, 1 H) 3.48-3.51 (m, 1 H) 3.62-3.70 (m, 1H) 3.92-4.03 (m, 1 H) 4.38 (d, 2 H) 5.23-5.35 (m, 1 H) 7.52-7.68 (m, 3H) 7.92 (s, 1 H) 9.12 (s, 3 H)

Example 409 Methyl1-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate,as a mixture of 2 diastereoisomers

To a mixture of Example 407 (105 mg, 202 μmol), DIPEA (180 μL, 1.0 mmol)in DCM (5 mL) was added methyl carbonochloridate (47 μL, 610 μmol), andthe mixture was stirred at until complete conversion. Water and DCM wereadded and the layers evaporated. The aqueous layer was extracted withDCM and the combined organic layers were evaporated to dryness. Theresidue was purified via preparative HPLC (method 1, LCMS, Rt: 1.19 min)to give 70.0 mg (60% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.61 (d, 3 H) 1.92 (s, 2 H) 3.34-3.54(m, 2 H) 3.61 (d, 3 H) 3.73-3.93 (m, 2 H) 4.39-4.61 (m, 3 H) 5.30 (s, 1H) 7.53-7.70 (m, 3 H) 7.94 (t, 1 H) 9.07-9.26 (m, 3 H).

LCMS, method 1, rt: 1.19 min, MS ES+ m/z=578 (M+H)⁺.

Example 410 Ethyl1-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate,as a Mixture of 2 Diastereoisomers

To a mixture of Example 407 (50.0 mg, 96.2 μmol), DIPEA (84 μL, 480μmol) in DCM (2.4 mL) was added ethyl carbonochloridate (31.3 mg, 289μmol), and the mixture was stirred at until complete conversion. Waterand DCM were added and the layers evaporated. The aqueous layer wasextracted with DCM and the combined organic layers were evaporated todryness. The residue was purified via preparative HPLC (method 1, LCMS,Rt: 1.25 min) to give 40.0 mg (70% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 1.19 (q, 3 H) 1.61 (d, 3 H) 1.91 (br.s., 2 H) 3.35-3.57 (m, 2 H) 3.71-3.91 (m, 2 H) 3.99-4.14 (m, 2 H)4.38-4.58 (m, 3 H) 5.30 (s, 1 H) 7.51-7.71 (m, 3 H) 7.94 (t, 1 H)9.07-9.24 (m, 3 H).

LCMS, method 1, rt: 1.25 min, MS ES+ m/z=592 (M+H)⁺.

Example 4113-{[(2S)-4-ethylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Example 350 (50 mg, 0.10 mmol) was dissolved in DCE (1 mL) at RT.Acetaldehyde (55 μL) and acetic acid (5 μL) were added and the reactionmixture stirred at RT for 30 minutes. STAB (63 mg, 0.30 mmol) was addedand the reaction stirred overnight. The reaction mixture was neutralisedwith saturated NaHCO₃ (2 mL) and extracted with DCM (2×2 mL). Thecombined organics were dried over magnesium sulphate, filtered andevaporated to give crude product. Purification by preparative HPLC(Method A) in two injections gave 11 mg (20% yield) of the titlecompound.

¹H NMR (500 MHz, DMSO-d6): δ [ppm] 1.01 (t, J=7.2, 3H), 1.61 (d, J=7.1,3H), 1.93 (t, J=10.6, 1H), 2.01 (td, J=11.3, 3.2, 1H), 2.35 (q, J=7.2,2H), 2.51 (s, 3H), 2.66-2.74 (m, 1H), 2.85-2.92 (m, 1H), 3.55 (td,J=11.2, 2.4, 1H), 3.77-3.86 (m, 2H), 4.07-4.15 (m, 2H), 5.25-5.34 (m,1H), 7.54 (d, J=1.3, 2H), 7.64 (d, J=1.2, 1H), 7.92 (t, J=1.4, 1H), 9.12(s, 2H), 9.15 (d, J=7.1, 1H).

LC-MS (Analytical Method A) Rt=2.17 min, MS (ESIpos): m/z=536.1 (M+H)⁺.

In analogy to the procedure described for Example 346, the followingexample was prepared using T3P and the corresponding carboxylic acid andprimary amine starting materials.

Ex. Structure Name Analytical Data 412

Tert-butyl (2R)-2- {[3-(5-methyl-1,3- thiazol-2-yl)-5- ({(1S)-1-[2-(trifluoromethyl) pyrimidin-5-yl] ethyl]carbamoyl) phenoxy]methyl}morpholine-4- carboxylate ¹H NMR (500 MHz, Chloroform- d): δ [ppm] 8.94(s, 2H), 7.90- 7.86 (m, 1H), 7.55-7.51 (m, 2H), 7.50-7.48 (m, 1H), 7.40-7.32 (m, 1H), 7.23-6.94 (m, 1H), 5.41-5.31 (m, 1H), 4.15- 3.80 (m, 5H),3.80-3.73 (m, 1H), 3.62-3.51 (m, 1H), 3.09- 2.63 (m, 2H), 2.53-2.49 (m,3H), 1.70 (d, J = 7.1 Hz, 3H), 1.47 (s, 9H). LCMS (Analytical Method F)Rt = 4.02 min, MS (ESIpos) m/z = 608 (M+H)⁺.

In analogy to the procedure described for Example 347, the followingexamples were prepared using TFA and the corresponding N-Boc protectedamine starting materials.

Ex. Structure Name Analytical Data 413

3-(5-methyl- 1,3-thiazol-2- yl)-5-[(2R)- morpholin-2- ylmethoxy]-N-{(1S)-1-[2- (trifluoromethyl) pyrimidin-5-yl] ethyl}benzamide ¹H NMR(500 MHz, Chloroform- d): δ [ppm] 8.93 (s, 2H), 7.84 (s, 1H), 7.54-7.49(m, 1H), 7.50-7.46 (m, 1H), 7.40-7.35 (m, 1H), 6.99 (d, J = 6.7 Hz, 1H),5.39-5.30 (m, 1H), 4.05 (dd, J = 9.9, 5.9 Hz, 1H), 3.99 (dd, J = 9.9,4.2 Hz, 2H), 3.97-3.86 (m, 2H), 3.75-3.65 (m, 1H), 3.06-2.99 (m, 1H),2.97-2.84 (m, 2H), 2.77 (dd, J = 12.0, 10.4 Hz, 1H), 2.50 (d, 3H), 1.69(d, J = 7.2 Hz, 3H). LCMS (Analytical Method D) Rt = 3.17 min, MS(ESIpos) m/z = 508 (M + H)⁺. 414

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(2S)- morpholin-2- ylmethoxy]-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl] ethyl}benzamide 1H NMR(500 MHz, Chloroform-d): δ [ppm] 7.92-7.89 (m, 1H), 7.82 (d, J = 8.7 Hz,1H), 7.74 (d, J = 8.7 Hz, 1H), 7.63- 7.57 (m, 1H), 7.56-7.52 (m, 1H),7.46 (d, J = 7.1 Hz, 1H), 7.44-7.42 (m, 1H), 5.65-5.54 (m, 1H),4.15-4.00 (m, 2H), 3.98-3.87 (m, 2H), 3.70 (td, J = 11.3, 2.7 Hz, 1H),3.07-3.01 (m, 1H), 2.98- 2.75 (m, 5H), 1.76 (d, J = 7.0 Hz, 3H), 1.36(t, J = 7.5 Hz, 3H). LCMS (Analytical Method F) Rt = 2.24 min, MS(ESIpos): m/z = 522.2 (M + H)+. 415

3-(5-ethyl-1,3- thiazol-2-yl)-5- [(2R)- morpholin-2- ylmethoxy]-N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl] ethyl}benzamide ¹H NMR(500 MHz, Chloroform-d): δ [ppm] 7.91-7.89 (m, 1H), 7.82 (d, J = 8.7 Hz,1H), 7.74 (d, J = 8.7 Hz, 1H), 7.62-7.58 (m, 1H), 7.55-7.52 (m, 1H),7.47-7.42 (m, 2H), 5.66-5.53 (m, 1H), 4.13-4.00 (m, 2H), 3.97-3.86 (m,2H), 3.70 (td, J = 11.3, 2.7 Hz, 1H), 3.07-3.01 (m, 1H), 2.99-2.74 (m,5H), 1.76 (d, J = 7.0 Hz, 3H), 1.36 (t, J = 7.5 Hz, 3H). LCMS(Analytical Method F) Rt = 2.21 min, MS (ESIpos): m/z = 522.3 (M + H)⁺.

In analogy to the procedure described for Example 366, the followingexamples were prepared using STAB and the corresponding amine andaldehyde or ketone starting materials.

Ex. Structure Name Analytical Data 416

3-{[(2R)-4- methylmorpholin- 2-yl]methoxy}- 5-(5-methyl-1,3-thiazol-2-yl)- N-{(1S)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide SFC Chiral Analysis (Method 16): 99.8% e.e. Rt = 4.06 min. ¹HNMR (500 MHz, Chloroform-d): δ [ppm] 8.93 (s, 2H), 7.88-7.84 (m, 1H),7.57-7.52 (m, 1H), 7.50 (d, J = 1.0 Hz, 1H), 7.41-7.36 (m, 1H), 6.82 (d,J = 6.6 Hz, 1H), 5.40-5.30 (m, 1H), 4.10 (dd, J = 9.9, 5.9 Hz, 1H), 4.04(dd, J = 9.9, 4.1 Hz, 1H), 4.01-3.91 (m, 2H), 3.81-3.72 (m, 1H),2.87-2.81 (m, 1H), 2.73- 2.67 (m, 1H), 2.54-2.50 (m, 3H), 2.34 (s, 3H),2.26-2.17 (m, 1H), 2.11-2.05 (m, 1H), 1.70 (d, J = 7.2 Hz, 3H). LCMS(Analytical Method F) Rt = 2.16 min, MS (ESIpos) 522 (M + H)⁺. 417

3-{[(2S)-4- methylmorpholin- 2-yl]methoxy}- 5-(5-methyl-1,3-thiazol-2-yl)- N-{(1S)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide SFC Chiral Analysis (Method 16): 100% e.e. Rt = 3.71 min. ¹HNMR (500 MHz, Chloroform-d): δ [ppm] 8.94 (s, 2H), 7.89-7.85 (m, 1H),7.58-7.54 (m, 1H), 7.53- 7.49 (m, 1H), 7.42-7.38 (m, 1H), 6.79 (d, J =6.3 Hz, 1H), 5.40-5.31 (m, 1H), 4.12 (dd, J = 9.6, 5.6 Hz, 1H),4.08-3.99 (m, 2H), 3.99- 3.93 (m, 1H), 3.84-3.75 (m, 1H), 2.91-2.85 (m,1H), 2.77-2.70 (m, 1H), 2.54-2.50 (m, 3H), 2.37 (s, 3H), 2.29-2.21 (m,1H), 2.14- 2.07 (m, 1H), 1.71 (s, 3H). LCMS (Analytical Method F) Rt =2.16 min, MS (ESIpos) 522 (M + H)⁺. 418

3-(5-Ethyl-1,3- thiazol-2-yl)-5- {[(2S)-4- methylmorpholin-2-yl]methoxy}- N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamide 1H NMR (500 MHz, Chloroform-d): δ [ppm] 7.92-7.89 (m, 1H),7.82 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.61 (dd, J = 2.4,1.5 Hz, 1H), 7.54-7.52 (m, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.43 (dd, J =2.3, 1.6 Hz, 1H), 5.65-5.48 (m, 1H), 4.15- 4.10 (m, 1H), 4.09-4.03 (m,1H), 4.00-3.93 (m, 2H), 3.79-3.72 (m, 1H), 2.90 (qd, J = 7.5, 0.9 Hz,2H), 2.87-2.80 (m, 1H), 2.71-2.65 (m, 1H), 2.34 (s, 3H), 2.25-2.16 (m,1H), 2.12-2.03 (m, 1H), 1.76 (d, J = 7.0 Hz, 3H), 1.36 (t, J = 7.5 Hz,3H). LCMS (Analytical Method F) Rt = 2.27 min, MS (ESIpos): m/z = 536.3(M + H)⁺. 419

3-(5-ethyl-1,3- thiazol-2-yl)-5- {[(2R)-4- methylmorpholin-2-yl]methoxy}- N-{(1R)-1-[6- (trifluoromethyl) pyridazin-3- yl]ethyl}benzamide ¹H NMR (500 MHz, Chloroform-d): δ [ppm] 7.84-7.83 (m, 1H),7.75 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 2.2,1.5 Hz, 1H), 7.48-7.45 (m, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.36 (dd, J =2.3, 1.5 Hz, 1H), 5.59-5.49 (m, 1H), 4.08- 4.03 (m, 1H), 4.01-3.96 (m,1H), 3.93-3.86 (m, 2H), 3.72-3.66 (m, 1H), 2.86-2.81 (m, 2H), 2.80- 2.76(m, 1H), 2.64-2.60 (m, 1H), 2.27 (s, 3H), 2.17-2.08 (m, 1H), 2.04-1.96(m, 1H), 1.69 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.5 Hz, 3H). LCMS(Analytical Method F) Rt = 2.27 min, MS (ESIpos): m/z = 536.3 (M + H)⁺.Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilised to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered with pharmaceuticallyacceptable carriers well known in the art using any effectiveconventional dosage unit forms, including immediate, slow and timedrelease preparations, orally, parenterally, topically, nasally,ophthalmic, optically, sublingually, rectally, vaginally, and the like.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known in the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatine typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatine,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, colouring agents, and flavouring agents such as peppermint, oil ofwintergreen, or cherry flavouring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavouring and colouringagents described above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more colouring agents; one or more flavouringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavouring and colouring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimise or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxylpropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al., “Compendium of Excipients forParenteral Formulations” PDA Journal of Pharmaceutical Science &Technology 1998, 52(5), 238-311; Strickley, R. G “ParenteralFormulations of Small Molecule Therapeutics Marketed in the UnitedStates (1999)—Part-1” PDA Journal of Pharmaceutical Science a Technology1999, 53(6), 324-349; and Nema, S. et al., “Excipients and Their Use inInjectable Products” PDA Journal of Pharmaceutical Science & Technology1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

-   acidifying agents (examples include but are not limited to acetic    acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);-   alkalinizing agents (examples include but are not limited to ammonia    solution, ammonium carbonate, diethanolamine, monoethanolamine,    potassium hydroxide, sodium borate, sodium carbonate, sodium    hydroxide, triethanolamine, trolamine);-   adsorbents (examples include but are not limited to powdered    cellulose and activated charcoal);-   aerosol propellants (examples include but are not limited to carbon    dioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃);-   air displacement agents (examples include but are not limited to    nitrogen and argon);-   antifungal preservatives (examples include but are not limited to    benzoic acid, butylparaben, ethylparaben, methylparaben,    propylparaben, sodium benzoate);-   antimicrobial preservatives (examples include but are not limited to    benzalkonium chloride, benzethonium chloride, benzyl alcohol,    cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl    alcohol, phenylmercuric nitrate and thimerosal);-   antioxidants (examples include but are not limited to ascorbic acid,    ascorbyl palmitate, butylated hydroxyanisole, butylated    hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl    gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde    sulfoxylate, sodium metabisulfite);-   binding materials (examples include but are not limited to block    polymers, natural and synthetic rubber, polyacrylates,    polyurethanes, silicones, polysiloxanes and styrene-butadiene    copolymers);-   buffering agents (examples include but are not limited to potassium    metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate    anhydrous and sodium citrate dihydrate);-   carrying agents (examples include but are not limited to acacia    syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup,    orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,    bacteriostatic sodium chloride injection and bacteriostatic water    for injection);-   chelating agents (examples include but are not limited to edetate    disodium and edetic acid);-   colourants (examples include but are not limited to FD&C Red No. 3,    FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No.    5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red);-   clarifying agents (examples include but are not limited to    bentonite);-   emulsifying agents (examples include but are not limited to acacia,    cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin,    sorbitan monooleate, polyoxyethylene 50 monostearate);-   encapsulating agents (examples include but are not limited to    gelatin and cellulose acetate phthalate);-   flavourants (examples include but are not limited to anise oil,    cinnamon oil, cocoa, menthol, orange oil, peppermint oil and    vanillin);-   humectants (examples include but are not limited to glycerol,    propylene glycol and sorbitol);-   levigating agents (examples include but are not limited to mineral    oil and glycerin);-   oils (examples include but are not limited to arachis oil, mineral    oil, olive oil, peanut oil, sesame oil and vegetable oil);-   ointment bases (examples include but are not limited to lanolin,    hydrophilic ointment, polyethylene glycol ointment, petrolatum,    hydrophilic petrolatum, white ointment, yellow ointment, and rose    water ointment);-   penetration enhancers (transdermal delivery) (examples include but    are not limited to monohydroxy or polyhydroxy alcohols, mono- or    polyvalent alcohols, saturated or unsaturated fatty alcohols,    saturated or unsaturated fatty esters, saturated or unsaturated    dicarboxylic acids, essential oils, phosphatidyl derivatives,    cephalin, terpenes, amides, ethers, ketones and ureas);-   plasticizers (examples include but are not limited to diethyl    phthalate and glycerol);-   solvents (examples include but are not limited to ethanol, corn oil,    cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid,    peanut oil, purified water, water for injection, sterile water for    injection and sterile water for irrigation);-   stiffening agents (examples include but are not limited to cetyl    alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl    alcohol, white wax and yellow wax);-   suppository bases (examples include but are not limited to cocoa    butter and polyethylene glycols (mixtures));-   surfactants (examples include but are not limited to benzalkonium    chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl    sulfate and sorbitan mono-palmitate);-   suspending agents (examples include but are not limited to agar,    bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl    cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,    kaolin, methylcellulose, tragacanth and veegum);-   sweetening agents (examples include but are not limited to    aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin    sodium, sorbitol and sucrose);-   tablet anti-adherents (examples include but are not limited to    magnesium stearate and talc);-   tablet binders (examples include but are not limited to acacia,    alginic acid, carboxymethylcellulose sodium, compressible sugar,    ethylcellulose, gelatin, liquid glucose, methylcellulose,    non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch);-   tablet and capsule diluents (examples include but are not limited to    dibasic calcium phosphate, kaolin, lactose, mannitol,    microcrystalline cellulose, powdered cellulose, precipitated calcium    carbonate, sodium carbonate, sodium phosphate, sorbitol and starch);-   tablet coating agents (examples include but are not limited to    liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose,    hydroxypropyl methylcellulose, methylcellulose, ethylcellulose,    cellulose acetate phthalate and shellac);-   tablet direct compression excipients (examples include but are not    limited to dibasic calcium phosphate);-   tablet disintegrants (examples include but are not limited to    alginic acid, carboxymethylcellulose calcium, microcrystalline    cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone,    sodium alginate, sodium starch glycollate and starch);-   tablet glidants (examples include but are not limited to colloidal    silica, corn starch and talc);-   tablet lubricants (examples include but are not limited to calcium    stearate, magnesium stearate, mineral oil, stearic acid and zinc    stearate);-   tablet/capsule opaquants (examples include but are not limited to    titanium dioxide);-   tablet polishing agents (examples include but are not limited to    carnuba wax and white wax);-   thickening agents (examples include but are not limited to beeswax,    cetyl alcohol and paraffin);-   tonicity agents (examples include but are not limited to dextrose    and sodium chloride);-   viscosity increasing agents (examples include but are not limited to    alginic acid, bentonite, carbomers, carboxymethylcellulose sodium,    methylcellulose, polyvinyl pyrrolidone, sodium alginate and    tragacanth); and-   wetting agents (examples include but are not limited to    heptadecaethylene oxycetanol, lecithins, sorbitol monooleate,    polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).    Combination Therapies

The term “combination” in the present invention is used as known topersons skilled in the art and may be present as a fixed combination, anon-fixed combination or kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein thesaid first active ingredient and the said second active ingredient arepresent together in one unit dosage or in a single entity. One exampleof a “fixed combination” is a pharmaceutical composition wherein thesaid first active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein the said first active ingredient and the said secondactive ingredient are present in more than one unit. One example of anon-fixed combination or kit-of-parts is a combination wherein the saidfirst active ingredient and the said second active ingredient arepresent separately. The components of the non-fixed combination orkit-of-parts may be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

The compounds of the present invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. The present invention relates also to suchcombinations.

For example, the compounds of the present invention can be combined withknown hormonal therapeutic agents.

In particular, the compounds of the present invention can beadministered in combination or as comedication with hormonalcontraceptives. Hormonal contraceptives can be administered via oral,subcutan, transdermal, intrauterine or intravaginal route, for exampleas Combined Oral Contraceptives (COCs) or Progestin-Only-Pills (POPs) orhormone-containing devices like implants, patches or intravaginal rings.

COCs include but are not limited to birth control pills or a birthcontrol method that includes a combination of an estrogen (estradiol)and a progestogen (progestin). The estrogenic part is in most of theCOCs ethinyl estradiol. Some COCs contain estradiol or estradiolvalerate.

Said COCs contain the progestins norethynodrel, norethindrone,norethindrone acetate, ethynodiol acetate, norgestrel, levonorgestrel,norgestimate, desogestrel, gestodene, drospirenone, dienogest, ornomegestrol acetate.

Birth control pills include for example but are not limited to Yasmin,Yaz, both containing ethinyl estradiol and drospirenone; Microgynon orMiranova containing levonorgestrel and ethinyl estradiol; Marveloncontaining ethinyl estradiol and desogestrel; Valette containing ethinylestradiol and dienogest; Belara and Enriqa containing ethinyl estradioland chlormadinonacetate; Qlaira containing estradiol valerate anddienogest as active ingredients; and Zoely containing estradiol andnormegestrol.

POPs are contraceptive pills that contain only synthetic progestogens(progestins) and do not contain estrogen. They are colloquially known asmini pills. POPs include but are not limited to Cerazette containingdesogestrel; Microlut containing levonorgestrel and Micronor containingnorethindrone.

Other Progeston-Only forms are intrauterine devices (IUDs), for exampleMirena containing levonorgestrel or injectables, for exampleDepo-Provera containing medroxyprogesterone acetate, or implants, forexample Implanon containing etonogestrel.

Other hormone-containing devices with contraceptive effect which aresuitable for a combination with the compounds of the present inventionare vaginal rings like Nuvaring containing ethinyl estradiol andetonogestrel or transdermal systems like a contraceptive patch, forexample Ortho-Evra or Apleek (Lisvy) containing ethinyl estradiol andgestodene.

A preferred embodiment of the present invention is the administration ofa compound of general formula (I) in combination with a COC or a POP orother Progestin-Only forms as well as vaginal rings or contraceptivepatches as mentioned above.

The compounds of the present invention can be combined with therapeuticagents or active ingredients, that are already approved or that arestill under development for the treatment and/or prophylaxis of diseaseswhich are related to or mediated by P2X3 receptor.

For the treatment and/or prophylaxis of urinary tract diseases, thecompounds of the present invention can be administered in combination oras comedication with any substance that can be applied as therapeuticagent in the following indications:

Urinary tract disease states associated with the bladder outletobstruction; urinary incontinence conditions such as reduced bladdercapacity, increased frequency of micturition, urge incontinence, stressincontinence, or bladder hyperreactivity; benign prostatic hypertrophy;prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactivebladder and symptoms related to overactive bladder wherein said symptomsare in particular increased urinary frequency, nocturia, urinary urgencyor urge incontinence; pelvic hypersensitivity; urethritis; prostatitis;prostatodynia; cystitis, in particular interstitial cystitis; idiopathicbladder hypersensitivity.

For the treatment and/or prophylaxis of overactive bladder and symptomsrelated to overactive bladder, the compounds of the present inventioncan be administered in combination or as comedication, independently orin addition to behavioral therapy like diet, lifestyle or bladdertraining, with anticholinergics like oxybutynin, tolterodine,propiverine, solifenacin, darifenacin, trospium, fesoterdine; β-3agonists like mirabegron; neurotoxins like onabutolinumtoxin A; orantidepressants like imipramine, duloxetine.

For the treatment and/or prophylaxis of interstitial cystitis, thecompounds of the present invention can be administered in combination oras comedication, independently or in addition to behavioral therapy likediet, lifestyle or bladder training, with pentosans like elmiron; NSAIDS(Non-Steroidal Antiinflammatory Drugs), either unselective NSAIDS likeibuprofen, diclofenac, aspirin, naproxen, ketoprofen, indomethacin; aswell as Cox-2 selective NSAIDS like Parecoxib, Etoricoxib, Celecoxib;antidepressants like amitriptyline, imipramine; or antihistamines likeloratadine.

For the treatment and/or prophylaxis of gynaecological diseases, thecompounds of the present invention can be administered in combination oras comedication with any substance that can be applied as therapeuticagent in the following indications:

dysmenorrhea, including primary and secondary dysmenorrhea; dyspareunia;endometriosis; endometriosis-associated pain; endometriosis-associatedsymptoms, wherein said symptoms are in particular dysmenorrhea,dyspareunia, dysuria, or dyschezia.

For the treatment and/or prophylaxis of dysmenorrhea, including primaryand secondary dysmenorrhea; dyspareunia; endometriosis andendometriosis-associated pain, the compounds of the present inventioncan be administered in combination or as comedication with painmedicaments, in particular NSAIDS like ibuprofen, diclofenac, aspirin,naproxen, ketoprofen, indomethacin; as well as Cox-2 selective NSAIDSlike Parecoxib, Etoricoxib, Celecoxib; or in combination with ovulationinhibiting treatment, in particular COCs as mentioned above orcontraceptive patches like Ortho-Evra or Apleek (Lisvy); or withprogestogenes like dienogest (Visanne); or with GnRH analogous, inparticular GnRH agonists and antagonists, for example leuprorelin,nafarelin, goserelin, cetrorelix, abarelix, ganirelix, degarelix; orwith androgens: danazol.

For the treatment and/or prophylaxis of diseases which are associatedwith pain, or pain syndromes, the compounds of the present invention canbe administered in combination or as comedication with any substancethat can be applied as therapeutic agent in the following indications:

pain-associated diseases or disorders like hyperalgesia, allodynia,functional bowel disorders (such as irritable bowel syndrome) andarthritis (such as osteoarthritis, rheumatoid arthritis and ankylosingspondylitis), burning mouth syndrome, burns, migraine or clusterheadache, nerve injury, traumatic nerve injury, post-traumatic injuries(including fractures and sport injuries), neuritis, neuralgia,poisoning, ischemic injury, interstitial cystitis, trigeminal neuralgia,small fiber neuropathy, diabetic neuropathy, chronic arthritis andrelated neuralgias, HIV and HIV treatment-induced neuropathy.

The compounds of the present invention can be combined with otherpharmacological agents and compounds that are intended to treatinflammatory diseases, inflammatory pain or general pain conditions.

In addition to well-known medicaments which are already approved and onthe market, the compounds of the present invention can be administeredin combination with inhibitors of PTGES (prostaglandin E synthase), withinhibitors of IRAK4 (interleukin-1 receptor-associated kinase 4) andwith antagonists of the prostanoid EP4 receptor (prostaglandin E2receptor 4).

In particular, the compounds of the present invention can beadministered in combination with pharmacological endometriosis agents,intended to treat inflammatory diseases, inflammatory pain or generalpain conditions and/or interfering with endometriotic proliferation andendometriosis associated symptoms, namely with inhibitors ofAldo-keto-reductase1C3 (AKR1C3) and with functional blocking antibodiesof the prolactin receptor.

For the treatment and/or prophylaxis of chronic cough and symptomsrelated to chronic cough, the compounds of the present invention can beadministered in combination or as comedication with cough suppressantslike dextromethorphan, benzonatate, codeine or hydrocodone; withinhalative agents to treat eosinophilic bronchitis, COPD or asthma likebudesonide, beclomethasone, fluticasone, theophylline, ipatropiumbromid,montelukast or salbutamol; with drugs like proton pump inhibitors whichare used to treat acid reflux, for example omeprazole, esomeprazole,lansoprazole, ranitidine, famotidine, cimetidine; and promotility agentssuch as metoclopramide; with nasal or topical glucocorticoids likefluticasone or mometasone or triamcinolone; or with oral antihistamineslike loratadine, fexofenadine or cetirizine.

The compounds of the present invention can be combined with otherpharmacological agents and compounds that are intended for thetreatment, prevention or management of cancer.

In particular, the compounds of the present invention can beadministered in combination with 131I-chTNT, abarelix, abiraterone,aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept,aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine,amifostine, aminoglutethimide, Hexyl aminolevulinate, amrubicin,amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensinII, antithrombin III, aprepitant, arcitumomab, arglabin, arsenictrioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan,bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide,bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximabvedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calciumlevofolinate, capecitabine, capromab, carboplatin, carfilzomib,carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib,cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir,cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine,copanlisib, crisantaspase, cyclophosphamide, cyproterone, cytarabine,dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib,daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab,depreotide, deslorelin, dexrazoxane, dibrospidium chloride,dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine,doxorubicin, doxorubicin+estrone, dronabinol, eculizumab, edrecolomab,elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide,epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta,eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine,etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim,fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide,folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant,gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide,gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron,granulocyte colony stimulating factor, histamine dihydrochloride,histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid,ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib,imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate,interferon alfa, interferon beta, interferon gamma, iobitridol,iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole,ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide,lenograstim, lentinan, letrozole, leuprorelin, levamisole,levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine,lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol,melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate,methoxsalen, methylaminolevulinate, methylprednisolone,methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin,mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphinehydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin,naloxone+pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine,neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide,nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab,octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole,ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone,oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin,palladium-103 seed, palonosetron, pamidronic acid, panitumumab,pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxyPEG-epoetin beta), pennbrolizunnab, pegfilgrastim, peginterferonalfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane,perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin,pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate,polyvinylpyrrolidone+sodium hyaluronate, polysaccharide-K, pomalidomide,ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone,procarbazine, procodazole, propranolol, quinagolide, rabeprazole,racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed,ramosetron, ramucirumab, ranimustine, rasburicase, razoxane,refametinib, regorafenib, risedronic acid, rhenium-186 etidronate,rituximab, romidepsin, romiplostim, romurtide, roniciclib, samarium(153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T,sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol,streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen,tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomabmerpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur,tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus,teniposide, testosterone, tetrofosmin, thalidomide, thiotepa,thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan,toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumabemtansine, treosulfan, tretinoin, trifluridine+tipiracil, trilostane,triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan,ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib,vinblastine, vincristine, vindesine, vinflunine, vinorelbine,vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres,zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

Furthermore, the compounds of the present invention can be combined withactive ingredients, which are well known for the treatment ofcancer-related pain and chronic pain. Such combinations include, but arenot limited to NSAIDS (either unselective NSAIDS like ibuprofen,diclofenac, aspirin, naproxen, ketoprofen and indomethacin; and Cox-2selective NSAIDS like Parecoxib, Etoricoxib and Celecoxib), step IIopiods like codeine phosphate, dextropropoxyphene, dihydro-codeine,Tramadol), step III opiods like morphine, fentanyl, buprenorphine,oxymorphone, oxycodone and hydromorphone; and other medications used forthe treatment of cancer pain like steroids as Dexamethasone andmethylprednisolone; bisphosphonates like Etidronate, Clodronate,Alendronate, Risedronate, and Zoledronate; tricyclic antidepressantslike Amitriptyline, Clomipramine, Desipramine, Imipramine and Doxepin;class I antiarrhythmics like mexiletine and lidocaine; anticonvulsantslike carbamazepine, Gabapentin, oxcarbazepine, phenytoin, pregabalin,topiramate, alprazolam, diazepam, flurazepam, pentobarbital andphenobarbital.

Methods of Treating

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to inhibit the P2X3receptor.

The present invention also provides a method for using the compounds ofthe present invention and compositions thereof, to selectively inhibitthe P2X3 receptor over the P2X2/3 receptor which means at least 3-foldselectivity over the P2X2/3 receptor.

The present invention also provides a method for using the preferredcompounds of the present invention and compositions thereof, toselectively inhibit the P2X3 receptor over the P2X2/3 receptor with atleast 10-fold selectivity over the P2X2/3 receptor. In addition to that,the present invention also provides a method of treating mammalianincluding human disorders and diseases using the more preferredcompounds of the present invention which show further advantageousproperties that are beneficial for their use as medicaments, such asdesirable pharmacokinetic profiles that provide suitable metabolicstability and oral bioavailability. In addition to that, a method oftreating mammalian including human disorders and diseases is providedusing even more preferred compounds of the present invention which showfurther advantageous properties that are beneficial for their use asmedicaments, such as desirable pharmacokinetic profiles that providesuitable metabolic stability and oral bioavailability, and at least oneadditional advantageous property chosen from an advantageouscardiovascular profile and a suitable CYP inhibition profile.

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalian includinghuman disorders and diseases which include but are not limited to:

-   -   genitourinary, gastrointestinal, respiratory, and pain-related        diseases, conditions and disorders;    -   gynecological diseases including dysmenorrhea (primary and        secondary dysmenorrhea), dyspareunia, endometriosis, and        adenomyosis; endometriosis-associated pain;        endometriosis-associated symptoms, wherein said symptoms are in        particular dysmenorrhea, dyspareunia, dysuria, or dyschezia;        endometriosis-associated proliferation; pelvic hypersensitivity;    -   urinary tract disease states associated with the bladder outlet        obstruction; urinary incontinence conditions such as reduced        bladder capacity, increased frequency of micturition, urge        incontinence, stress incontinence, or bladder hyperreactivity;        benign prostatic hypertrophy; prostatic hyperplasia;        prostatitis; detrusor hyperreflexia; overactive urinary bladder        and symptoms related to overactive urinary bladder wherein said        symptoms are in particular increased urinary frequency,        nocturia, urinary urgency or urge incontinence; pelvic        hypersensitivity; urethritis; prostatitis; prostatodynia;        cystitis, in particular Interstitial cystitis; idiopathic        bladder hypersensitivity;    -   cancer-related pain;    -   Epilepsy, partial and generalized seizures;    -   respiratory disorders including asthma, chronic obstructive        pulmonary disease, pulmonary fibrosis, acute cough, chronic        cough including chronic idiopathic and chronic refractory cough,        bronchospasm;    -   gastrointestinal disorders including irritable bowel syndrome        (IBS), inflammatory bowel disease (IBD), biliary colic and other        biliary disorders, renal colic, diarrhea-dominant IBS;        gastroesophageal reflux, gastrointestinal distension, Crohn's        disease and the like;    -   neurodegenerative disorders such as Alzheimer's disease,        Multiple Sclerosis, Parkinson's disease, Brain ischemia and        traumatic brain injury;    -   pruritus.

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat pain-associatedmammalian including human disorders and diseases which include but notlimited to

-   -   pain-associated diseases or disorders selected from the group        consisting of hyperalgesia, allodynia, functional bowel        disorders (such as irritable bowel syndrome), gout, arthritis        (such as osteoarthritis, rheumatoid arthritis and ankylosing        spondylitis), burning mouth syndrome, burns, migraine or cluster        headaches, nerve injury, traumatic nerve injury, post-traumatic        injuries (including fractures and sport injuries), neuritis,        neuralgias, poisoning, ischemic injury, interstitial cystitis,        cancer, trigeminal neuralgia, small fiber neuropathy, diabetic        neuropathy, chronic arthritis and related neuralgias, HIV and        HIV treatment-induced neuropathy, pruritus; impaired wound        healing and disease of the skeleton like degeneration of the        joints.

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalian,including human disorders and diseases which are associated with pain,or pain syndromes which are in particular:

-   -   pain syndromes (including acute, chronic, inflammatory and        neuropathic pain), preferably inflammatory pain, low back pain        surgical pain, visceral pain, dental pain, periodontitis,        premenstrual pain, endometriosis-associated pain, pain        associated with fibrotic diseases, central pain, pain due to        burning mouth syndrome, pain due to burns, pain due to migraine,        cluster headaches, pain due to nerve injury, pain due to        neuritis, neuralgias, pain due to poisoning, pain due to        ischemic injury, pain due to interstitial cystitis, cancer pain,        pain due to viral, parasitic or bacterial infections, pain due        to traumatic nerve-injury, pain due to post-traumatic injuries        (including fractures and sport injuries), pain due to trigeminal        neuralgia, pain associated with small fiber neuropathy, pain        associated with diabetic neuropathy, postherpetic neuralgia,        chronic lower back pain, neck pain phantom limb pain, pelvic        pain syndrome, chronic pelvic pain, neuroma pain, complex        regional pain syndrome, pain associated with gastrointestinal        distension, chronic arthritic pain and related neuralgias, and        pain associated with cancer, Morphine-resistant pain, pain        associated with chemotherapy, HIV and HIV treatment-induced        neuropathy; and pain associated with diseases or disorders        selected from the group consisting of hyperalgesia, allodynia,        functional bowel disorders (such as irritable bowel syndrome)        and arthritis (such as osteoarthritis, rheumatoid arthritis and        ankylosing spondylitis).

The present invention relates to a method for using the compounds of thepresent and compositions thereof to treat inflammation, in particularneurogenic inflammation. The term “inflammation” is also understood toinclude any inflammatory disease, disorder or condition per se, anycondition that has an inflammatory component associated with it, and/orany condition characterized by inflammation as a symptom, including,inter alia, acute, chronic, ulcerative, specific, allergic, infection bypathogens, immune reactions due to hypersensitivity, entering foreignbodies, physical injury, and necrotic inflammation, and other forms ofinflammation known to those skilled in the art. The term thus alsoincludes, for the purposes of this invention, inflammatory pain, paingenerally and/or fever. The present invention relates to a method forusing the compounds of the present invention and compositions thereof totreat fibromyalgia, myofascial disorders, viral infections (e.g.influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterialinfections, fungal infections, surgical or dental procedures, arthritis,osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onsetrheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin'sdisease, systemic lupus erythematosus, vasculitis, pancreatitis,nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, woundhealing, dermatitis, eczema, stroke, autoimmune diseases, allergicdisorders, rhinitis, ulcers, mild to moderately active ulcerativecolitis, familial adenomatous polyposis, coronary heart disease,sarcoidosis and any other disease with an inflammatory component. Thepresent invention relates to a method for using the compounds of thepresent invention and compositions thereof to treat mammalian, includinghuman disorders and diseases which are not linked to inflammatorymechanisms, such as in the reduction of bone loss in a subject. Diseasesthat may be mentioned in this regard include osteoporosis,osteoarthritis, Paget's disease and/or periodontal diseases.

Based on the P2X3 receptor inhibitory activity of compounds of thepresent invention, the present invention relates to a method for usingthe compounds of the present invention and compositions thereof to treatpain, fever and inflammation of a variety of conditions includingrheumatic fever, symptoms associated with influenza or other viralinfections, common cold, low back and neck pain, dysmenorrhea, headache,migraine (acute and prophylactic treatment), toothache, sprains andstrains, myositis, neuralgia, synovitis, arthritis, including rheumatoidarthritis, juvenile rheumatoid arthritis, degenerative joint diseases(osteoarthritis), acute gout and ankylosing spondylitis, acute, subacuteand chronic musculoskeletal pain syndromes such as bursitis, burns,injuries, and pain following surgical (post-operative pain) and dentalprocedures as well as the preemptive treatment of surgical pain. Thepain may be mild pain, moderate pain, severe pain, musculoskeletal pain,complex regional pain syndrome, neuropathic pain, back pain such asvisceral pain including acute visceral pain, neuropathies, acute trauma,chemotherapy-induced mononeuropathy pain states, polyneuropathy painstates (such as diabetic peripheral neuropathy and/or chemotherapyinduced neuropathy), autonomic neuropathy pain states, pheriphaeralnervous system (PNS) lesion or central nervous system (CNS) lesion ordisease related pain states, polyradiculopathies of cervical, lumbar orsciatica type, cauda equina syndrome, piriformis syndrome, paraplegia,quadriplegia, pain states related to various Polyneuritis conditionsunderlying various infections, chemical injuries, radiation exposure,underlying disease or deficiency conditions (such as beriberi, vitamindeficiencies, hypothyroidism, porphyria, cancer, HIV, autoimmune diseasesuch as multiple sclerosis and spinal-cord injury, fibromyalgia, nerveinjury, ischaemia, neurodegeneration, stroke, post stroke pain,inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder(GERD), irritable bowel syndrome, inflammatory bowel disease, overactivebladder, pelvic hypersensitivity, urinary incontinence, cystitis,stomach, duodenal ulcer, muscle pain, pain due to colicky and referredpain. The present invention relates to a method for using the compoundsof the present invention and compositions thereof to treat hemophilicarthropathy and Parkinson's disease.

A preferred embodiment of the present invention relates to a method forusing the compounds of the present invention and compositions thereof,to treat a gynaecological disease, preferably dysmenorrhea, dyspareuniaor endometriosis, endometriosis-associated pain, or otherendometriosis-associated symptoms, wherein said symptoms are inparticular dysmenorrhea, dyspareunia, dysuria, or dyschezia.

Another preferred embodiment of the present invention relates to amethod for using the compounds of the present invention and compositionsthereof, to treat a urinary tract disease, in particular overactivebladder or cystitis, preferably interstitial cystitis.

Another preferred embodiment of the present invention relates to amethod for using the compounds of the present invention and compositionsthereof, to treat a respiratory disorder, preferably cough, inparticular chronic cough.

Another preferred embodiment of the present invention relates to amethod for using the compounds of the present invention and compositionsthereof, to treat arthritis, in particular rheumatoid arthritis andankylosing spondylitis.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving acondition, disease or disorder such as a gynaecological disease, urinarytract disease, respiratory disorder or arthritis.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of disorders and/or disease which are mediatedby the P2X3 receptor, by standard toxicity tests and by standardpharmacological assays for the determination of treatment of theconditions identified above in mammals, and by comparison of theseresults with the results of known medicaments that are used to treatthese conditions, the effective dosage of the compounds of thisinvention can readily be determined for treatment of each desiredindication. The amount of the active ingredient to be administered inthe treatment of one of these conditions can vary widely according tosuch considerations as the particular compound and dosage unit employed,the mode of administration, the period of treatment, the age and sex ofthe patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, preferably from about 0.01 mg/kg to about 20 mg/kg body weightper day. A preferred administration of the compound of the presentinvention includes but is not limited to 0.1 mg/kg to about 10 mg/kgbody weight per day. Clinically useful dosing schedules will range fromone to three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Apreferred oral unit dosage for an administration of the compounds of thepresent invention includes but is not limited to 0.1 mg/kg to about 10mg/kg body weight one to three times a day to once a week. The averagedaily dosage for administration by injection, including intravenous,intramuscular, subcutaneous and parenteral injections, and use ofinfusion techniques will preferably be from 0.01 to 200 mg/kg of totalbody weight. The average daily rectal dosage regimen will preferably befrom 0.01 to 200 mg/kg of total body weight. The average daily vaginaldosage regimen will preferably be from 0.01 to 200 mg/kg of total bodyweight. The average daily topical dosage regimen will preferably be from0.1 to 200 mg administered between one to four times daily. Thetransdermal concentration will preferably be that required to maintain adaily dose of from 0.01 to 200 mg/kg. The average daily inhalationdosage regimen will preferably be from 0.01 to 100 mg/kg of total bodyweight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Preferably, the diseases treated with said method are gynaecologicaldisorders, more preferably dysmenorrhea, dyspareunia or endometriosis,endometriosis-associated pain, or other endometriosis-associatedsymptoms, wherein said symptoms are in particular dysmenorrhea,dyspareunia, dysuria, or dyschezia. Further diseases which can betreated with said method are osteoarthritis, diabetic neuropathy,burning mouth syndrome, gastroesophageal reflux, migraine disorders,chronic cough, asthma, pruritus, irritable bowel disease, overactiveurinary bladder, prostatic hyperplasia, interstitial cystitis.

Preferably, the method of treating the diseases mentioned above is notlimited to the treatment of said disease but also includes the treatmentof pain related to or associated with said diseases.

The compounds of the present invention can be used in particular intherapy and prevention, i.e. prophylaxis, of genitourinary,gastrointestinal, respiratory or pain-related disease, condition ordisorder.

Methods of testing for a particular pharmacological or pharmaceuticalproperty are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

Biological Assays

Examples were tested in selected biological assays one or more times.Unless stated otherwise, when tested more than once, data are reportedas either average values or as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

Intracellular Calcium Measurement to Assess Antagonist Activity at HumanP2X3 and Human P2X2/3 Receptors

A fluorescent imaging plate reader (FLEX/FLIPR station; MolecularDevices) was used to monitor intracellular calcium levels using thecalcium-chelating dye Fluo-4 (Molecular Probes). The excitation andemission wavelengths used to monitor fluorescence were 470-495 nm and515-575 nm, respectively. Cells expressing purinergic receptors P2X3(human) or P2X2/3 (human) were plated at a density of 15,000 cells/wellin collagen-coated 384-well plates approximately 20 hours beforebeginning the assay. On the day of the assay, 20 μl of Loading buffer(Hank's balanced salt solution, 20 mM HEPES, 0.5 mM CaCl₂, 0.5 mM MgCl₂,0.1% BSA, 5 mM probenecid, 10 mM D-glucose monohydrate, 2 μM Fluo-4, and5 units/mL, hexokinase, pH=7.4) was added and cells dye-loaded for 90min at 37° C. The dye supernatant was removed and replaced with 45 μlprobenecid buffer (Hank's balanced salt solution, 20 mM HEPES, 0.5 mMCaCl₂, 0.5 mM MgCl₂, 0.1% BSA, 5 mM probenecid, 10 mM D-glucosemonohydrate, pH=7.4). The test compound was added in a volume of 5 μland allowed to incubate for 30 min at 37° C. The final assay DMSOconcentration is 1%. The agonist, α,β-Me-ATP, was added in a volume of20 μl at a concentration representing the EC₈₀ value. The fluorescencewas measured for an interval of 90 sec at 2 sec intervals and analyzedbased on the increase in peak relative fluorescence units (RFU) comparedto the basal fluorescence. Peak fluorescence was used to determine theresponse to agonist obtained at each concentration of test compound bythe following equation:%Response=100*(RFU_((test compound))−RFU_((control))/RFU_((DMSO))−RFU_((control)))

The Examples were tested in triplicates per plate and mean values wereplotted in Excel XLFit to determine IC₅₀ values at the human P2X3 andhuman P2X2/3 receptors, percentage of maximal inhibition and the Hillcoefficients.

Patent Example hP2X3 IC₅₀ (nM) hP2X2/3 IC₅₀ (nM) 1 4 76 2 19 251 3 261106 4 9 98 5 16 346 6 4 38 7 8 106 8 3 90 9 7 145 10 7 185 11 8 163 12283 10000 13 21 1102 14 8 88 15 6 147 16 38 1707 17 35 1005 18 34 427 1919 749 20 35 486 21 71 445 22 132 987 23 30 1106 24 36 332 25 39 975 268 297 27 25 280 28 48 121 29 79 580 30 38 485 31 173 10000 32 24 1781 3329 912 34 111 2124 35 460 10000 36 14 306 37 55 1176 38 55 1145 39 811646 40 16 383 41 130 1592 42 129 1565 43 50 2688 44 11 370 45 212 151046 10 389 47 82 621 48 14 451 49 132 1525 50 77 982 51 74 1389 52 194564 53 318 2740 54 66 10000 55 8 325 56 148 10000 57 25 2840 58 4 461 5913 507 60 11 578 61 14 428 62 85 1436 63 4 118 64 53 984 65 3 54 66 356295 67 186 10000 68 44 1617 69 15 937 70 3 78 71 15 315 72 11 330 73 4101 74 14 1107 75 38 6638 76 201 5789 77 10 183 78 6 83 79 9 413 80 12339 81 3 34 82 28 380 83 125 1164 84 26 527 85 10 36 86 12 144 87 15 11988 30 217 89 11 199 90 111 710 91 19 133 92 24 317 93 8 385 94 7 132 952 129 96 18 1077 97 15 1687 98 1 19 99 2 27 100 6 16 101 15 60 102 10 57103 2 14 104 51 377 105 6 39 106 16 41 107 9 17 108 11 83 109 235 2412110 114 1451 111 16 380 112 61 772 113 43 387 114 38 414 115 15 187 116210 6430 117 36 883 118 198 1134 119 24 190 120 14 104 121 79 279 122106 1167 123 46 164 124 27 165 125 3 27 126 34 532 127 111 536 128 10 91129 3 33 130 74 1349 131 134 730 132 75 2051 133 177 10000 134 15 210135 35 209 136 196 2780 137 26 328 138 11 559 139 8 962 140 33 1295 14143 2201 142 6 222 143 84 3047 144 825 10000 145 271 4461 146 45 159 1476 132 148 33 794 149 21 936 150 12 83 151 31 333 152 45 523 153 27 304154 18 130 155 40 2267 156 5 163 157 17 534 158 21 1939 159 28 1233 16028 1007 161 32 632 162 5 74 163 5 83 164 60 1107 165 81 1923 166 40 461167 72 893 168 19 1600 169 9 70 170 165 2020 171 26 573 172 31 2107 1735 311 174 11 790 175 23 1274 176 29 607 177 14 887 178 39 1880 179 13703 180 31 1399 181 19 1181 182 63 1943 183 7 398 184 6 128 185 4 123186 10 247 187 7 218 188 5 164 189 8 258 190 7 207 191 61 364 192 12 910193 2705 10000 194 46 579 195 380 10000 196 19 293 197 1152 10000 198 30245 199 1544 10000 200 30 546 201 16 1854 202 42 1710 203 36 1561 204 782 205 4 272 206 31 1676 207 5 87 208 2 89 209 30 1470 210 12 1012 211395 10000 212 4 46 213 5 81 214 47 3392 215 16 992 216 14 928 217 251750 218 7 281 219 2 199 220 62 2502 221 26 1358 222 4 108 223 3 109 2249 569 225 16 1145 226 6 59 227 13 161 228 5 54 229 44 2276 230 2 209 2316 706 232 13 759 233 16 753 234 7 152 235 18 70 236 76 1012 237 177 537238 38 397 239 1420 2171 240 12 35 241 12 533 242 2 22 243 117 259 24475 555 245 34 142 246 266 982 247 205 963 248 44 273 249 11 57 250 15299 251 5 38 252 75 275 253 99 598 254 28 116 255 254 449 256 136 1494257 47 324 258 4 38 259 10 102 260 2 14 261 45 317 262 85 383 263 33 170264 81 530 265 104 696 266 41 367 267 14 173 268 14 392 269 2 35 270 25100 271 45 230 272 19 128 273 28 254 274 75 873 275 21 191 276 10 76 2776 96 278 2 23 279 115 956 280 51 682 281 26 198 282 8 209 283 10 379 2844 57 285 113 760 286 87 1234 287 35 275 288 150 1314 289 192 1768 290 31368 291 1320 10000 292 6 52 293 63 1155 294 101 1060 295 55 557 296 6133 297 56 933 298 62 781 299 37 575 300 78 820 301 91 1714 302 6 145303 5 38 304 7 27 305 9 44 306 42 464 307 16 103 308 153 2586 309 8 70310 116 1678 311 8 35 312 9 83 313 11 200 314 8 192 315 8 160 316 21 250317 45 952 318 32 476 319 76 1324 320 33 627 321 120 1447 322 49 498 32325 411 324 46 552 325 26 235 326 21 378 327 10 239 328 12 274 329 5 120330 5 170 331 7 191 332 4 174 333 4 122 334 4 132 335 13 541 336 14 443337 13 257 338 4 72 339 5 251 340 3 103 341 41 1242 342 40 1892 343 13510000 344 34 987 345 7 99 346 13 334 347 9 1521 348 7 760 349 23 545 35014 1162 351 16 690 352 18 1139 353 7 427 354 25 1034 355 9 956 356 29643 357 5 310 358 57 1441 359 6 200 360 10 455 361 14 1254 362 8 1014363 12 717 364 16 943 365 21 1049 366 18 977 367 13 506 368 84 1094 36911 328 370 41 1007 371 24 1173 372 19 1211 373 21 2827 374 55 2557 37511 185 376 32 898 377 5 273 378 60 3752 379 42 2755 380 32 2880 381 16954 382 13 432 383 2 35 384 3 75 385 3 28 386 24 811 387 19 461 388 181353 389 18 1614 390 17 804 391 19 840 392 11 411 393 24 1033 394 823983 395 30 1312 396 22 1803 397 15 1362 398 17 1795 399 69 1722 400 591477 401 30 1466 402 21 1251 403 56 2108 404 44 533 405 17 1558 406 262026 407 15 1681 408 32 1710 409 22 976 410 22 906 411 20 697 412 68710000 413 597 10000 414 29 2272 415 10 2177 416 227 10000 417 434 10000418 23 1556 419 9 1136Solubility Assays

The aqueous solubility of a drug substance is an importantphysicochemical parameter that has a significant role in variousphysical and biological processes. In vivo, inadequate solubility of thedesired dose results in incomplete absorption of orally administereddrugs and causes low oral bioavailability. Solubility data are used toassess absorption, distribution, metabolism and elimination parametersand to develop formulations for safety screens, pre-clinical and earlyclinical use.

High Throughput Determination of Aqueous Test Compound Solubility (100mmolar in DMSO)

The assay was run in a 96-well plate format. Each well was filled withan individual compound.

All pipetting steps were performed using a robot platform.

100 μl of a 10 mmolar solution of test compound in DMSO wereconcentrated by vacuum evaporation and resolved in 10 μl DMSO to gain a100 mmolar DMSO solution. 990 μl 0.1 M phosphate buffer pH 6.5 wereadded. The content of DMSO amounts to 1%. The multititer plate was puton a shaker and mixed for 24 hrs at room temperature. 150 μl of thesuspension were transferred to a filtration plate. After filtrationusing a vacuum manifold the filtrate was diluted 1:400 and 1:8000. Asecond microtiter plate with 20 μl of a 10 mM solution of test compoundin DMSO served for calibration. Two concentrations (0.005 μM and 0.0025μM) were prepared by dilution in DMSO/water 1:1 and used forcalibration. Filtrate and calibration plates were quantified byHPLC-MS/MS.

Chemicals:

Preparation of 0.1 M Phosphate Buffer pH 6.5:

61.86 g NaCl and 39.54 mg KH₂PO₄ were solved in water and filled up to 1l. The mixture was diluted 1:10 with water and the pH adjusted to 6.5 byNaOH.

Materials: Millipore MultiScreen_(HTS)-HV Plate 0.45 μm

Chromatographic conditions were as follows:

-   HPLC column: Ascentis Express C18 2.7 μm 4.6×30 mm-   Injection volume: 1 μl-   Flow: 1.5 ml/min-   Mobile phase: acidic gradient    -   A: Water/0.05% HCOOH    -   B: Acetonitrile/0.05% HCOOH    -   0 min→95% A 5% B    -   0.75 min→5% A 95% B    -   2.75 min→5% A 95% B    -   2.76 min→95% A 5% B    -   3 min→95% A 5% B

The areas of sample- and calibration injections were determined by usinga mass spectrometry (AB Sciex Triple Quad 6500) software (AB SCIEX:Discovery Quant 2.1.3. and Analyst 1.6.1). The solubility value (inmg/l) was calculated from the sample- and calibration curves.

Equilibrium Shake Flask Solubility Assay

Thermodynamic solubility was determined by an equilibrium shake flaskmethod [Literature: Edward H. Kerns and Li Di (2008) Solubility Methodsin: Drug-like Properties: Concepts, Structure Design and Methods, p276-286. Burlington, Mass.: Academic Press].

A saturated solution of the test compound in 0.1 M phosphate buffer (pH6.5) was prepared and the solution was mixed for 24 h to ensure thatequilibrium has been reached. The solution was centrifuged to remove theinsoluble fraction and the concentration of the compound in solution wasdetermined by HPLC-UV using a standard calibration curve.

To prepare the sample, 1.5 mg solid compound was weighed in a 4 ml glassvial. 1 ml 0.1 M phosphate buffer (pH 6.5) was added. The suspension wasput on a stirrer and mixed for 24 hrs at room temperature. The solutionwas centrifuged afterwards. To prepare the sample for the standardcalibration, 0.6 mg solid sample was dissolved in 19 mlacetonitrile/water 1:1. After sonification the solution was filled upwith acetonitrile/water 1:1 to 20 ml.

Sample and standards were quantified by HPLC with UV-detection. For eachsample two injection volumes (5 and 50 μl) in triplicates were made.Three injection volumes (5 μl, 10 μl and 20 μl) were made for thestandard.

Chemicals

Preparation of 0.1 M phosphate buffer pH 6.5:

61.86 g NaCl and 39.54 mg KH₂PO₄ were solved in water and filled up to 1l. The mixture was diluted 1:10 with water and the pH adjusted to 6.5 byNaOH.

Chromatographic conditions were as follows:

-   HPLC column: Xterra MS C18 2.5 μm 4.6×30 mm-   Injection volume: Sample: 3×5 μl and 3×50 μl    -   Standard: 5 μl, 10 μl, 20 μl-   Flow: 1.5 ml/min-   Mobile phase: acidic gradient    -   A: Water/0.01% TFA    -   B: Acetonitrile    -   0 min→95% A 5% B    -   0-3 min→35% A 65% B, linear gradient    -   3-5 min→35% A 65% B, isocratic    -   5-6 min→95% A 5% B, isocratic-   UV detector: wavelength near the absorption maximum (between 200 and    400 nm)

The areas of sample- and standard injections as well as the calculationof the solubility value (in mg/l) were determined by using HPLC software(Waters Empower 2 FR).

Bidirectional Caco-2 Cell Permeability Assay

Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded ata density of 4.5×10⁴ cell per well on 24 well insert plates, 0.4 μm poresize, and grown for 15 days in Dulbecco's modified Eagle mediumsupplemented with 10% fetal bovine serum, 1% GlutaMAX (100×, purchasedfrom GIBCO), 100 U/ml penicillin, 100 μg/ml streptomycin (purchased fromGIBCO) and 1% non-essential amino acids (100×). Cells were maintained at37° C. in a humidified 5% CO₂ atmosphere. Medium was changed every 2-3days. Before running the permeability assay, the culture medium wasreplaced by a serum free hepes-carbonate transport buffer (pH 7.2). Testcompounds were dissolved in DMSO and added to the donor chamberrepresenting either the apical or basolateral compartment in a finalconcentration of 2 μM. Before and after 2 h incubation at 37° C. sampleswere taken from both compartments (donor and receiver chamber). Analysisof compound concentrations was done after precipitation with methanol.Analysis was performed by high-pressure liquid chromatography and atandem mass spectrometric detector using an Agilent 1200 liquidchromatography system and an AB Sciex API4000 triple-quadrupole massspectrometer applying the parameters, which were optimized to achievemaximum signal intensity of the corresponding test compound.Permeability (Papp) was calculated in the apical to basolateral (A→B)and basolateral to apical (B→A) directions. The apparent permeabilitywas calculated using following equation:P_(app)=(V_(r)/P_(o))·(1/S)·(P₂/t) where V_(r) is the volume of mediumin the receiver chamber; P_(o) is the measured peak area of the testcompound in the donor chamber at t=0 h; S the surface area of themonolayer; P₂ is the measured peak area of the test compound in theacceptor chamber after 2 h of incubation; and t is the incubation time.The efflux ratio basolateral (B) to apical (A) was calculated bydividing the P_(app) B-A by the P_(app) A-B.

The bidirectional Caco-2 cell permeability assay is a well-establishedmethod for predicting the in vivo absorption of drugs across the gutwall by measuring the rate of transport of a compound across the Caco-2monolayer. Since differentiated Caco-2 cells express functional effluxtransport proteins like P-gp, they are also used for identification ofcompounds with efflux liabilities. Intestinal efflux can decreasesystemic plasma concentrations of an orally dosed compound by affectingintestinal absorption of a compound. Preferred examples of the presentinvention show permeability Papp A-B >50 nm/s and efflux ratio <5. Morepreferred examples of the present invention show permeability PappA-B >80 nm/s and efflux ratio <2.

TABLE 1 Bidirectional Caco-2 cell permeability assay of test compoundsP_(app) A-B P_(app) B-A Efflux Example (nm/s) (nm/s) ratio 11 155 2161.4 19 249 163 0.65 48 180 212 1.2 185 102 181 1.8 339 153 214 1.4 348135 190 1.4 347 5.8 209 36 419 104 175 1.7In Vitro Metabolic Stability AssaysDetermination of in vitro metabolic stability in microsomes (includingcalculation of hepatic in vivo blood clearance (CL) and of maximal oralbioavailability (F_(max)))

The in vitro metabolic stability of test compounds was determined byincubating them at 1 μM in a suspension liver microsomes in 100 mMphosphate buffer, pH 7.4 (NaH₂PO₄× H₂O+Na₂HPO₄×2H₂O) and at a proteinconcentration of 0.5 mg/mL at 37° C. The microsomes were activated byadding a co-factor mix containing 8 mM Glucose-6-Phosphate, 4 mM MgCl₂;0.5 mM NADP and 1 IU/ml G-6-P-Dehydrogenase in phosphate buffer, pH 7.4.The metabolic assay was started shortly afterwards by adding the testcompound to the incubation at a final volume of 1 mL. Organic solvent inthe incubations was limited to ≤01% dimethylsulfoxide (DMSO) and ≤1%acetonitrile. During incubation, the microsomal suspensions werecontinuously shaken at 580 rpm and aliquots were taken at 2, 8, 16, 30,45 and 60 min, to which equal volumes of cold methanol were immediatelyadded. Samples were frozen at −20° C. overnight, subsequentlycentrifuged for 15 minutes at 3000 rpm and the supernatant was analyzedwith an Agilent 1200 HPLC-system with LCMS/MS detection.

The half-life of a test compound was determined from theconcentration-time plot. From the half-life (kel: slope ofconcentration-time plot; half-life=ln 2/kel) the intrinsic clearanceswere calculated. Together with the additional parameters liver bloodflow, specific liver weight and microsomal protein content the hepaticin vivo blood clearance (CL) and the maximal oral bioavailability (Fmax)were calculated for the different species. The hepatic in vivo bloodclearance (CLblood) and the maximal oral bioavailability (Fmax) wascalculated using the following formulae: CL′intrinsic [ml/(min*kg)]=kel[1/min]/((mg protein/volume of incubation [ml])*fu,inc)*(mgprotein/liver weight [g])*(specific liver weight [g liver/kg bodyweight]); CLblood well-stirred [L/(h*kg)]=(QH[L/(h*kg)]*fu,blood*CL′intrinsic [L/(h*kg)])/(QH[L/(h*kg)]+fu,blood*CL′intrinsic [L/(h*kg)]); Fmax=1−CLblood/QH andusing the following parameter values: Liver blood flow (QH)−1.32 L/h/kg(human), 2.1 L/h/kg (dog), 4.2 L/h/kg (rat); specific liver weight—21g/kg (human), 39 g/kg (dog), 32 g/kg (rat); microsomal proteincontent—40 mg/g.; fu,inc and fu,blood is taken as 1.

Determination of in vitro metabolic stability in rat hepatocytes(including calculation of hepatic in vivo blood clearance (CL))

Hepatocytes from Han Wistar rats were isolated via a 2-step perfusionmethod. After perfusion, the liver was carefully removed from the rat:the liver capsule was opened and the hepatocytes were gently shaken outinto a Petri dish with ice-cold Williams' medium E (WME). The resultingcell suspension was filtered through sterile gaze in 50 mL falcon tubesand centrifuged at 50×g for 3 min at room temperature. The cell pelletwas resuspended in 30 mL WME and centrifuged through a Percoll® gradientfor 2 times at 100×g. The hepatocytes were washed again with WME andresuspended in medium containing 5% FCS. Cell viability was determinedby trypan blue exclusion.

For the metabolic stability assay liver cells were distributed in WMEcontaining 5% FCS to glass vials at a density of 1.0×10⁶ vital cells/mL.The test compound was added to a final concentration of 1 μM. Duringincubation, the hepatocyte suspensions were continuously shaken at 580rpm and aliquots were taken at 2, 8, 16, 30, 45 and 90 min, to whichequal volumes of cold methanol were immediately added. Samples werefrozen at −20° C. overnight, subsequently centrifuged for 15 minutes at3000 rpm and the supernatant was analyzed with an Agilent 1200HPLC-system with LCMS/MS detection.

The half-life of a test compound was determined from theconcentration-time plot. From the half-life (kel: slope ofconcentration-time plot; half-life=ln 2/kel) the intrinsic clearanceswere calculated. Together with the additional parameters liver bloodflow, amount of liver cells in vivo and in vitro. The hepatic in vivoblood clearance (CLblood) and the maximal oral bioavailability (Fmax)was calculated using the following formulae: CL′intrinsic[ml/(min*kg)]=kel [1/min]/((cellno/volume of incubation[ml])*fu,inc)*(cellno/liver weight [g])*(specific liver weight [gliver/kg body weight]); CLblood well-stirred [L/(h*kg)]=(QH[L/(h*kg)]*fu,blood*CL′intrinsic [L/(h*kg)])/(QH[L/(h*kg)]+fu,blood*CL′intrinsic [L/(h*kg)]); Fmax=1−CLblood/QH andusing the following parameter values: Liver blood flow (QH)—4.2 L/h/kgrat; specific liver weight—32 g/kg rat body weight; liver cells invivo—1.1×108 cells/g liver, liver cells in vitro—1.0×106/ml; fu,inc andfu, blood is taken as 1.

Investigation of In Vitro Metabolic Stability in Cryopreserved HumanHepatocytes (Including Calculation of Hepatic In Vivo Blood Clearance(CL))

Cryopreserved Hepatocytes (e.g. from Celsis InVitroTechnologies) werebriefly thawed, washed with 45 mL pre-warmed in vitro GRO HT medium andcentrifuged for 5 min at 50×g. The cell pellet was resuspended in 5 mLof Krebs-Henseleit Butter (KHB). Cell viability was determined by trypanblue exclusion.

For the metabolic stability assay liver cells were distributed inWilliams' medium E (WME) containing 5% FCS to glass vials at a densityof 0.5×10⁶ vital cells/mL. The test compound was added to a finalconcentration of 1 μM. During incubation, the hepatocyte suspensionswere continuously shaken at 580 rpm and aliquots were taken at 2, 8, 16,30, 45 and 90 min, to which equal volumes of cold methanol wereimmediately added. Samples were frozen at −20° C. overnight,subsequently centrifuged for 15 minutes at 3000 rpm and the supernatantwas analyzed with an Agilent 1200 HPLC-system with LCMS/MS detection.

The half-life of a test compound was determined from theconcentration-time plot. From the half-life (kel: slope ofconcentration-time plot; half-life=ln 2/kel) the intrinsic clearanceswere calculated. Together with the additional parameters liver bloodflow, amount of liver cells in vivo and in vitro. The hepatic in vivoblood clearance (CL) and the maximal oral bioavailability (Fmax) wascalculated. The hepatic in vivo blood clearance (CLblood) and themaximal oral bioavailability (Fmax) was calculated using the followingformulae: CL′intrinsic [ml/(min*kg)]=kel [1/min]/((cellno/volume ofincubation [ml])*fu,inc)*(cellno/liver weight [g])*(specific liverweight [g liver/kg body weight]); CLblood well-stirred [L/(h*kg)]=(QH[L/(h*kg)]*fu,blood*CL′intrinsic [L/(h*kg)])/(QH[L/(h*kg)]+fu,blood*CL′intrinsic [L/(h*kg)]); Fmax=1−CLblood/QH andusing the following parameter values: Liver blood flow—1.32 L/h/kghuman; specific liver weight—21 g/kg rat body weight; liver cells invivo—1.1×108 cells/g liver, liver cells in vitro—1.0×106/ml.; fu,inc andfu,blood is taken as 1.

Liver Microsomal and Hepatocytes Stability Assays

Metabolic instability is often the main clearance mechanism ofxenobiotica leading to a high CL and low bioavailability which mayeventually result in a short half-life and a low exposure after oraladministration. Thus, reducing the susceptibility of metabolicdegradation usually leads to a more favourable pharmacokinetic profile.When using liver microsomes as incubation matrix main phase I metabolicreactions, typically oxidoreductive reactions by cytochrome P450 enzymesand flavin mono-oxygenases (FMO) and hydrolytic reactions byesterases/amidases/epoxidhydrolases, are described. When the incubationof the test compound is performed in a hepatocyte matrix all potentialhepatic metabolic processes (phase I and phase II) are covered.Preferred examples of the present invention show metabolic stability(given as Fmax) of ≥40% Fmax in human liver microsome as well as inhuman and rat hepatocyte preparations. More preferred examples of thepresent invention show metabolic stability (given as Fmax) of 50% Fmaxin human liver microsome as well as in human and rat hepatocytepreparations.

TABLE 2 In vitro metabolic stability values of test compounds In vitrometabolic stability Human liver Rat hepatocyte Example microsome Fmax(%) Fmax (%) 11 57 52 26 67 56 48 99 68 163 100 53 183 74 43 185 77 58188 68 56 339 94 52 340 90 64 348 54 58 419 74 51Human Liver Cytosol Stability Assay

The use of human liver cytosol to evaluate the metabolic stability of anew drug candidate shows effectively its susceptibility to non-CYPmediated oxidative biotransformation. If a compound is a strongsubstrate of aldehyde oxidase or xanthine oxidase, metabolic clearancevia this pathway can lead to a low bioavailability in human. As bothenzymes are active in human liver cytosol, susceptibility of testcompounds to aldehyde or xanthine oxidase mediated metabolism can bepredicted and compared by determination of turnover of test compound aswell as formation of the corresponding oxidised metabolite afterincubation in human liver cytosol. More preferred examples of thepresent invention have <15% turnover after 4 hrs incubation time inhuman liver cytosol preparations.

Method description: Human liver cytosol (pooled, >30 male and femaledonors) was incubated with individual test compounds in order to comparethe extent of depletion of test compound and formation of the respectiveoxidised metabolite. The incubation medium consisted of 50 mM potassiumphosphate buffer (pH 7.4) and 1 mg/mL human liver cytosolic protein. Anincubation volume of 1000 μL was used. The test compound was added froma stock solution in acetonitrile at 1 or 10 μM concentration in theincubation. Incubations were performed at 37° C. Reactions were stoppedat 0 h and 4 h after incubation by addition of 100 μL acetonitrile to250 μL of incubation mixture. Precipitated proteins were removed bycentrifugation at approximately 3000 rpm. The supernatants were storedat approximately −20° C. until they were analysed. The determination ofdepletion of the test compound and formation of the metabolites wasperformed by chromatographic separation (Aquity BEH300 C4 50×2.1 mm, 1.7μm, gradient: 10 mM ammonium acetate/acetonitrile) and simultaneous UVand mass spectrometric detection using an Accela UPLC pump and UVdetector coupled to a LTQ-FT mass spectrometer (Thermo FisherScientific, Bremen, Germany).

Data analysis: The depletion of the test compound and formation of thecorresponding metabolites were determined by decrease or increase of thecorresponding peak area in the chromatogram after UV detection atapproximately 300 nm 4 h after incubation compared to that at 0 h afterincubation. The identity of the analytes under the peaks were confirmedby LC-MS/MS.

TABLE 3 Stability of test compound in human liver cytosol [%] Testcompound Formation of turnover oxidised metabolites Example after 4 hafter 4 h 266 (WO2009110985) 45 48 11 12 3.9 26 12 2.5 48 6.8 2.3 3485.6 5.6CYP Inhibition and Pre-Incubation CYP Inhibition Assays

Use of in vitro assays to evaluate the inhibition potential of new drugcandidates towards CYP-mediated metabolism has been shown to beeffective as part of a strategy to minimise the chances of druginteractions with co-administered drugs. The inhibitory potency of thetest compound towards 5 human cytochrome P450 isoforms (CYP1A2, 2C8,2C9, 2D6, and 3A4) was determined. More preferred examples of thepresent invention have CYP inhibition IC₅₀≥10 μM.

For CYP3A4 time dependent inhibitory potential was also tested byapplying a 30 min pre-incubation time of the test compound inmetabolically active incubation system. If a time-dependent inhibitionof CYP3A4 is observed, this is a hint of an irreversible mechanism-basedinhibition of the CYP3A4 activity by the test compound. More preferredexamples of the present invention have pre-incubation CYP inhibitionIC₅₀≥20 μM.

Method Description CYP Inhibition Assay

Human liver microsomes (pooled, >30 male and female donors) wereincubated with individual CYP isoform-selective standard probes(phenacetin for CYP1A2, amodiquine for CYP2C8, diclofenac for CYP2C9,dextromethorphan for CYP2D6 and midazolam for CYP3A4) in the absence andpresence of increasing concentrations of the test compound in order tocompare the extent of formation of the respective metabolite. Inaddition, a set of incubation in the absence of test compound was usedas a negative control. Furthermore, the inhibitory potency of standardinhibitors was included as positive controls (fluvoxamine for CYP1A2,montelukast for CYP2C8, sulfaphenazole for CYP2C9, fluoxetine forCYP2D6, ketoconazole for CYP3A4 and mibefradil forCYP3A4-preincubation). Incubation conditions (protein and probesubstrate concentration, incubation time) were optimised with regard tolinearity and metabolite turnover. Incubation medium consisted of 50 mMpotassium phosphate buffer (pH 7.4) containing 1 mM EDTA, NADPHregenerating system (1 mM NADP, 5 mM glucose 6-phosphate, glucose6-phosphate dehydrogenase (1.5 U/mL). Sequential dilutions andincubations were performed on a Genesis Workstation (Tecan, Crailsheim,FRG) in 96-well plates at 37° C. A final incubation volume of 200 μL wasused. Reactions were stopped by addition of 100 μL acetonitrilecontaining the respective internal standard. Precipitated proteins wereremoved by centrifugation of the well plate, supernatants were combinedand analyses were performed by LC-MS/MS. The LC-MS/MS quantification ofthe metabolites paracetamol (CYP1A2), desethylamodiaquine (CYP2C8),4-hydroxydiclofenac (CYP2C9), dextrorphan (CYP2D6), and1-hydroxyidazolam (CYP3A4) was performed with a PE SCIEX API 3000LC/MS/MS system (Applied Biosystems, MDS Sciex, Concord, Ontario,Canada).

Data analysis: The CYP-mediated activities in the presence of inhibitorswere expressed as percentages of the corresponding control values. Asigmoid-shaped curve was fitted to the data, and the enzyme inhibitionparameter IC₅₀ was calculated using a nonlinear least-squares regressionanalysis of the plot of percent control activity versus concentration ofthe test inhibitor.

TABLE 4 Inhibitory effect of test compounds to CYP enzymes IC₅₀ [μM]CYP3A4 with Example CYP1A2 CYP2C8 CYP2C9 CYP2D6 CYP3A4 preincubation333 >20 >20 19.8 >20 >20 18 (WO20091109 85)  11 >20 >20 >20 >20 >20 >20 19 >20 >20 >20 >20 >20 >20  26 >20 >20 >20 >20 >20 >20 48 >20 >20 >20 >20 >20 >20 163 >20 >20 >20 >20 >20 >20 185 >2019 >20 >20 >20 >20Patch-Clamp hERG Channel Electrophysiology Assay

Malfunction of cardiac ion channels can, in some cases, lead to cardiacarrhythmias. Investigation of the effects of compounds on cardiac ionchannels is therefore recommended or mandatory (hERG) under safetypharmacology guidelines¹. The hERG potassium channel is the mostprominent target for drug-induced QT-prolongation^(2,3), an unwantedside effect which can lead to the life-threatening torsade de pointestype arrhythmias. ¹The ICH Steering Committee, The nonclinicalevaluation of the potential for delayed ventricular repolarizaiton (QTinterval prolongation) by human pharmaceuticals, S7B, 10 Jun.2004²Roden, D M., New England Journal of Medicine, 350 10; 2004:1013-1022.³Netzer, R., Ebneth, A., Bischoff, U., Pongs, O., DrugDiscovery Today, 2001, 6, 78-84.

The objective of this assay was to evaluate whether test compound has anintrinsic effect on the hERG K⁺ current in stably transfected HEK293cells. Test compound was evaluated in vitro at concentrations of 0.1, 1and 10 μmol/L (approximately 5-6 minutes per concentration).

The whole-cell voltage-clamp technique (automated 8-channel system:Patchliner, Nanion, Germany) was used with PatchControlHT software(Nanion) to control the Patchliner system and to handle data aquisitionand analysis. Voltage-clamp control was provided by two EPC-10 quadroamplifiers under control of the PatchMasterPro software (both: HEKAElektronik, Lambrecht, Germany) and with NPC-16 medium resistance (˜2MW) chips (Nanion) serving as planar substrate at room temperature.hERG-mediated inward tail currents were elicited by hyperpolarizingvoltage steps from +20 mV to −120 mV (duration 500 ms); holdingpotential was −80 mV, activating potential was +20 mV (duration 1000ms), clamp protocol was repeated every 12 s. Composition ofextracellular solution (in mmol/L): NaCl 140, KCl 4, CaCl₂ 2, MgCl₂ 1,glucose 5, HEPES 10, pH 7.4 (NaOH); composition of intracellularsolution (in mmol/L): NaCl 10, KCl 50, KF 60, EGTA 20, HEPES 10, pH 7.2(KOH). The effects of test compound were compared to predrug controlvalues (i.e. no test compound present) and to those induced by thepositive control E-4031, a potent and selective hERG K+ channel blocker(Sanguinetti M C, Jurkiewicz N K. Two components of cardiac delayedrectifier K⁺ current. Differential sensitivity to block by class IIIantiarrhythmic agents. J Gen Physiol 1990; 96:195-215).

Exposure of HEK293 cells stably transfected with the hERG K⁺ channel totest compound was associated with concentration-dependent inhibition ofthe hERG-mediated tail current amplitude. The concentration (μM) of testcompound that reached half-maximal inhibitory concentrations (IC₅₀) wasused to evaluate whether test compound has an intrinsic effect on thehERG K+ current. More preferred examples of the present invention havehERG IC₅₀>5 μM.

Rat CFA In Vivo Model

Male Sprague Dawley rats were used. Mechanical hyperalgesia was inducedby injecting 25 μl of Complete Freund's Adjuvant (CFA) into the plantarsurface of one hind paw. Mechanical hyperalgesia was measured using thePressure Application Measurement apparatus (Ugo Basile, Gemonio, Italy).Briefly, a linearly increasing pressure was applied to an area of ˜50mm2 of the plantar side of the hind paw until a behavioural response(paw withdrawal) was observed or until the pressure reached 1000 gf. Thepressure at which the behavioural response occurred was recorded as the“Paw Withdrawal Threshold” (PWT). Both CFA-injected and contralateralPWTs were determined for each rat, in each treatment group and at eachtime point of the studies. Mechanical hyperalgesia testing was performedbefore injecting CFA, 22 hours after CFA treatment (pre-drug baseline)and 2, 4 and 6 hours after compound dosing. Compounds were dosed 24hours after CFA injection. Data were expressed as the mean PWT for eachtreatment group and at each time point. Data were analysed by performinga repeated measures two way ANOVA (time×treatment). Planned comparisonof means (each versus vehicle) was performed by using a Dunnett's posthoc test, provided that a main effect was detected. For p values lessthan 0.05 the results were deemed to be statistically significant.

Preclinical in vivo efficacy models, such as the rat CFA in vivo model,are used in drug discovery to evaluate efficacy response and demonstratedesirable duration of action of new drug candidates. More preferredexamples of the present invention show rat CFA in vivo efficacy in the‘Paw withdrawal threshold 6 hours post drug’ measure when dosed at 3mg/kg p.o.

TABLE 5 Rat CFA in vivo model PWT data for test compounds Paw Paw humanwithdrawal withdrawal P2X3 threshold threshold receptor 6 hour-postDose, 6 hour-post Example IC₅₀ vehicle p.o. drug 11  8 nM 514 ± 34 gf 3mg/kg 639 ± 48 gf (*) 48 14 nM 430 ± 22 gf 3 mg/kg 817 ± 69 gf (****)185  4 nM 489 ± 22 gf 3 mg/kg 630 ± 81 (*) 348  7 nM 512 ± 15 gf 3 mg/kg633 ± 59 gf (*) 333 14 nM 426 ± 20 gf 3 mg/kg 565 ± 74 gf (ns)(WO2009110985) 333 14 nM 452 ± 23 gf 3 mg/kg 549 ± 42 (ns)(WO2009110985) * p < 0.05, **** p < 0.0001, Dunnett's post-hoc test,different from vehicle group, ns: not significant

TABLE 6 Rat CFA in vivo model PWT data for Example 348 at lower dose PawPaw human withdrawal withdrawal P2X3 threshold threshold receptor 6hour-post 6 hour-post Example IC₅₀ vehicle Dose, p.o. drug 348 7 nM 512± 15 gf   3 mg/kg 633 ± 59 gf (*) 348 7 nM 512 ± 15 gf   1 mg/kg 601 ±28 gf (**) 348 7 nM 512 ± 15 gf 0.3 mg/kg 599 ± 47 gf (*) * p < 0.05, **p < 0.01, Dunnett's post-hoc test, different from vehicle group, ns: notsignificantMouse CFA In Vivo Model

Female C57BL/6 mice were used to assess the effects of P2X3 receptorantagonists on CFA-induced mechanical hyperalgesia. 30 μL of CompleteFreud's Adjuvant (CFA, 1 mg/mL) were injected into the plantar surfaceof one hind paw. Mechanical hyperalgesia was measured using von Freyfilaments. Briefly, von Frey filaments were being used to stimulate theanimal's hindpaw and a behavioural response was measured depending onthe strength of the von Frey filament used. The strength of the filamentwas expressed in [g] and the threshold was recorded when a response ofthe animal was observed. Both CFA-injected and contralateral responsethresholds were determined for each mouse and in each treatment group 72hrs after CFA-injection. Compound application was done p.o. b.i.d.,starting one hour before CFA injection. Data were expressed as the meanthreshold for each treatment group. Data were analysed by performing aone way ANOVA over the different dose groups. Planned comparison ofmeans (each versus vehicle) was performed by using a Dunnett's post hoctest, provided that a main effect was detected. For p values less than0.05 the results were deemed to be statistically significant.

Example Dose Efficacy mouse CFA model Vehicle 0.179 g ± 0.044 11 25mg/kg, p.o. 0.682 g ± 0.122 (*) * p < 0.05 different from vehicle groupRat Dyspareunia Model

Dyspareunia was surgically induced in female Sprague Dawley rats byautotransplanting on abdominal arteries small pieces of uterine horn,that grow into vascularized cysts. The visceromotor response (VMR) tovaginal distension was used in conscious animals as an objective measureof vaginal sensitivity.

Briefly, animals in estrus phase were surgically implanted with biopsiesof left uterine horn (3×3 mm) around alternate cascade mesentericarteries that supply the small intestine (4 pieces) and on the wall ofthe distal colon (2 pieces). To measure VMR response, 2 Teflon-coatedwire electrodes were sutured in the external oblique abdominal muscle,and tunneled subcutaneously to be exteriorized at the base of the neckfor future access. On the day of VMR assessment, a lubricated smallballoon (1 cm length) was inserted into the mid-vaginal canal. Theballoon catheter was secured to the base of the tail and connected to avolume controller/timing device (infusion pump) for balloon distension.The vaginal balloon was inflated to ramp intensities of distension (0.05ml increments every 20 sec.) to a maximal volume of 0.8 ml. Theelectrodes were connected to an amplifier (Animal Bio Amp,ADInstrunnents), and the abdominal electromyographic signal was recordedusing a data acquisition system (PowerLab, ADInstrunnents) for off-lineanalysis using LabChart version 7. The number of abdominal musclecontractions was counted manually for each 0.1 ml distension step, as anindex of vaginal pain.

Example 11 or vehicle were dosed orally, twice daily (b.i.d.), during 2consecutive weeks, from week 4 to week 5 post-implantation of uterinehorn pieces. Example 11 was dosed at 15 mg/kg b.i.d., and vehicle (tween80/0.5% carboxymethylcellulose in water (5/95, vol/vol)), was dosed at 5ml/kg b.i.d. VMR/vaginal distension testing were then performed 5(on-drug) and 6 (off-drug) weeks post-implantation, when the animalswere in proestrus phase.

Statistical Analysis

All data were expressed as mean±standard deviation (s.d.), for thenumber (n) of measured rats per group. Analyses were done by running theGraphPad Prism 6.03 software. Two (2) parameters were analyzed for eachanimal: 1) the cumulative number of abdominal contractions wascalculated and plotted against vaginal distension volume; 2) thecorresponding area under the curve (AUC) was calculated using GraphPadPrism version 6.03. A Grubbs' test was performed on individual AUCvalues to reveal potential outliers. Repeated measures 2-Way-Analysis ofVariance (ANOVA) was used to analyze the cumulative number ofcontractions (distension volume×treatment). Planned comparison of means(matched-volume versus vehicle) was performed using a Bonferroni posthoc test, provided that a main effect was detected. A non-parametricMann-Whitney t test was used to compare AUC means versus vehicle. For pvalues less than 0.05, the results were considered statisticallysignificant.

Results

In vehicle-treated animals (5 ml/kg oral, b.i.d.), the cumulative numberof abdominal contractions increased as a function of vaginal distensionvolume, 5 and 6 weeks post-implantation of uterine horn pieces,confirming the existence of vaginal hyperalgesia. Example 11-treatedanimals (15 mg/kg oral, b.i.d. during 2 weeks) presented a decreasedvaginal hyperalgesia compared to vehicle-treated animals. Indeed, adecrease in the cumulative number of abdominal contractions was observedin response to matched—distension volume, associated with a significantdecrease in corresponding AUC (see table below). This decrease invaginal hyperalgesia was observed 5 weeks post-implantation (p<0.05),while the animals were still on-drug treatment, and 6 weeks later(p<0.01), while the animals were off-drug treatment.

Treatment group Vehicle Example 11 Time post- (5 ml/kg oral, (15 mg/kgoral, implantation b.i.d. for 2 weeks) b.i.d. for 2 weeks) 5 weeks 4.56± 3.20 (14) 2.08 ± 1.63* (14) 6 weeks 3.83 ± 2.54 (15) 1.64 ± 1.53**(17)

Effect of Example 11 on areas under the curve (AUC, plot of individualcumulative number of abdominal contractions against vaginal distensionvolume) 5 and 6 weeks post-implantation of uterine horn pieces. Datarepresent mean±s.d. (n in each group). * p<0.05, ** p<0.01 differentfrom Vehicle group.

In Vivo Pharmacokinetics in Rats, Dogs and Monkeys

For in vivo pharmacokinetic experiments test compounds were administeredto male Wistar rats, Beagle dogs or Cynomolgus monkeys intravenously atdoses of 0.3 to 1 mg/kg and intragastral at doses of 0.5 to 10 mg/kgformulated as solutions using solubilizers such as PEG400 inwell-tolerated amounts.

In the rat also cassette administrations of up to 3 compounds giventogether in low doses were performed.

For pharmacokinetics after intravenous administration test compoundswere given in the male rat as i.v. bolus and in dogs and monkeys asshort term infusion (15 min). Blood samples were taken e.g. at 2 min, 8min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h afterdosing from the vena jugularis (rat) or vena saphena (dog, monkey). Forpharmacokinetics after intragastral administration test compounds weregiven intragastral to fasted rats, dogs and monkeys. Blood samples weretaken e.g. at 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and24 h after dosing. Blood was collected into Lithium-Heparintubes(Monovetten®, Sarstedt) and centrifuged for 15 min at 3000 rpm. Analiquot of 100 μL from the supernatant (plasma) was taken andprecipitated by addition of 400 μL cold acetonitril and frozen at −20°C. over night. Samples were subsequently thawed and centrifuged at 3000rpm, 4° C. for 20 minutes. Aliquots of the supernatants were taken foranalytical testing using an Agilent HPLC-system with LCMS/MS detection.PK parameters were calculated by non-compartmental analysis using a PKcalculation software, (e.g. Phoenix WinNonlin®, Certara USA, Inc.).

PK parameters derived from concentration-time profiles after i.v.:CLplasma (in L/kg/h): Total plasma clearance of test compound calculatedby dose (in μg/kg) divided by area under the concentration-time curvefrom t=0 h to infinity (extrapolated) (AUCinf in μg*h/L); CLblood: Totalblood clearance of test compound: CLplasma*Cp/Cb (in L/kg/h) with Cp/Cbbeing the ratio of test compound concentrations in plasma and blood. PKparameters directly taken or calculated from concentration time profilesafter i.g.: Cmax: Maximal plasma concentration (directly taken from theprofile in mg/L); Cmaxnorm: Cmax divided by the administered dose (inkg/L); Tmax: Time point at which Cmax was observed (in h). Parameterscalculated from both, i.v. and i.g. concentration-time profiles:AUCnorm: Area under the concentration-time curve from t=0 h to infinity(extrapolated) divided by the administered dose (in kg*h/L);AUC(0−tlast)norm: Area under the concentration-time curve from t=0 h tothe last time point for which plasma concentrations could be measureddivided by the administered dose (in kg*h/L); t1/2: terminal half-life(in h); F: oral bioavailability: AUCnorm after intragastraladministration divided by AUCnorm after intravenous administration (in%).

Pharmacokinetics describes the relationship between the dose and theunbound drug concentration at the site of action, and the time course ofdrug concentration in the body. Drug disposition is a broad term thatcovers all the processes by which the body handles foreign chemicals(including drugs). These are absorption, distribution, metabolism andexcretion (ADME).

The terminal half-life (t1/2) after oral and intravenous dosing andbioavailability (BA) are important pharmacokinetic properties of drugs.Preferred examples of the present invention show elimination half-life≥6 hours and bioavailability ≥50% in dog. More preferred examples of thepresent invention have elimination half-life ≥7 hours andbioavailability ≥70% in dog.

TABLE 7 Dog pharmacokinetic properties of test compounds Dog t½ Dog t½Dog Bioavailability Example Dose, p.o. Dose, i.v. p.o. [hour] i.v.[hour] (BA) [%]  11 1 mg/kg 0.5 mg/kg 12 8.8 70 348 1 mg/kg 0.5 mg/kg9.4 11 74Cyclophosphamide-induced Overactive Bladder(Rats)/Cyclophosphamide-induced Cystitis (Rats)

The aim of this study is to test the efficacy on P2X3 receptorantagonists on overactive bladder as well as on cystitis incyclophosphamide-treated rats.

The experimental setup is adapted to a previous descripted protocol(Lecci A et al, Br J Pharmacol 130: 331-38, 2000).

Briefly, female Sprague Daley rats (˜200 g) are housed under normalconditions for laboratory rats in a 12:12-h light:dark cycle. The testcompound is administrated by oral gavage (30 mg/kg) one hour beforeapplication of cyclophosphamide (100 mg/kg) by i.v. injection.Additional 1.5 hours after cyclophosphamide administration each rat istransferred to metabolic cage and voiding frequency is recorded for thenext 15 hours. The micturition/per hour is recorded and the AUC duringthe plateau phase of the micturition (4-10 hours after transfer tometabolic cages) is calculated for each animal with GraphPad Prism 6programme.

The invention claimed is:
 1. A compound of general formula (I):

wherein: R¹ is a halogen atom, C₁-C₄-alkyl or C₃-C₆-cycloalkyl, whereinsaid C₁-C₄-alkyl is optionally substituted with 1-5 halogen atoms whichare the same or different; R² is —C₂-C₆-alkyl-OR⁴,—(CH₂)_(q)—(C₃-C₇-cycloalkyl), —(CH₂)_(q)-(6- to 12-memberedheterobicycloalkyl), —(CH₂)_(q)-(4- to 7-membered heterocycloalkyl),—(CH₂)_(q)-(5- to 10-membered heteroaryl) or —C₂-C₆-alkynyl, whereinsaid —(CH₂)_(q)—(C₃-C₇-cycloalkyl), —(CH₂)_(q)-(6- to 12-memberedheterobicycloalkyl) and —(CH₂)_(q)-(4- to 7-membered heterocycloalkyl)are optionally substituted with one or more substituents which are thesame or different, at any ring carbon atom and selected from the groupconsisting of C₁-C₄ alkyl optionally substituted with 1-5 halogen atomswhich are the same or different, a halogen atom, —NR^(a)R^(b), COOR⁵ andoxo (═O), wherein any ring nitrogen atom, if present in said—(CH₂)_(q)-(6- to 12-membered heterobicycloalkyl) and —(CH₂)_(q)-(4- to7-membered heterocycloalkyl), is independently substituted with R^(c);and wherein said —(CH₂)_(q)-(5- to 10-membered heteroaryl) is optionallysubstituted with one or more substituents which are the same ordifferent, and selected from the group consisting of C₁-C₄-alkyloptionally substituted with 1-5 halogen atoms which are the same ordifferent, a halogen atom, —NR^(a)R^(b) and —COOR⁵; R³ is hydrogen orC₁-C₄-alkyl optionally substituted with 1-5 halogen atoms which are thesame or different; R⁴ and R⁵ are independently hydrogen or C₁-C₄-alkyl;R^(a) and R^(b) are independently hydrogen or C₁-C₄-alkyl; R^(c) ishydrogen, C₁-C₄-alkyl optionally substituted with 1-5 halogen atomswhich are the same or different, —C(O)O—C₁-C₄-alkyl, or—C(O)—C₁-C₄-alkyl; A is 5- to 10-membered heteroaryl which is optionallysubstituted with one or more substituents, which are the same ordifferent, and selected from the group consisting of a halogen atom,C₁-C₃-alkyl, and C₁-C₃-alkoxy, wherein said C₁-C₃-alkyl and C₁-C₃-alkoxyare optionally substituted with 1-5 halogen atoms which are the same ordifferent; and q is an integer of 0, 1, or 2, or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or salt thereof, or a mixtureof any of the foregoing.
 2. The compound according to claim 1, which isof formula (Ia):

wherein A, R¹, R² and R³ are as defined in claim 1, or an isomer,enantiomer, diastereomer, racemate, hydrate, solvate, or salt thereof,or a mixture of any of the foregoing.
 3. The compound according to claim1, wherein A is an optionally substituted 5- or 6-membered heteroaryl,or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate, orsalt thereof, or a mixture of any of the foregoing.
 4. The compoundaccording to claim 1, wherein R¹ is C₁-C₄-alkyl, or an isomer,enantiomer, diastereomer, racemate, hydrate, solvate, or salt thereof,or a mixture of any of the foregoing.
 5. The compound according to claim1, wherein R³ is C₁-C₄-alkyl, or an isomer, enantiomer, diastereomer,racemate, hydrate, solvate, or salt thereof, or a mixture of any of theforegoing.
 6. The compound according to claim 1, wherein R² is—C₂-C₃-alkyl-OR⁴, —CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl,—(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or —C₂-C₄-alkynyl,wherein said —CH₂—(C₃-C4-cycloalkyl), C₃-C₄-cycloalkyl and—(CH₂)_(q)-(4- to 6-membered heterocycloalkyl) are optionallysubstituted with one or more substituents which are the same ordifferent, at any ring carbon atom, and wherein any ring nitrogen atom,if present in said —(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), isindependently substituted with R^(c); and q is an integer of 0, or anisomer, enantiomer, diastereomer, racemate, hydrate, solvate, or saltthereof, or a mixture of any of the foregoing.
 7. The compound accordingto claim 1, wherein A is an optionally substituted 5- or 6-memberedheteroaryl; and R¹ is C₁-C₄-alkyl, or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or salt thereof, or a mixtureof any of the foregoing.
 8. The compound according to claim 1, wherein Ais an optionally substituted 5- or 6-membered heteroaryl; and R³ isC₁-C₄-alkyl, or an isomer, enantiomer, diastereomer, racemate, hydrate,solvate, or salt thereof, or a mixture of any of the foregoing.
 9. Thecompound according to claim 1, wherein A is an optionally substituted 5-or 6-membered heteroaryl; R¹ is C₁-C₄-alkyl; and R³ is C₁-C₄-alkyl, oran isomer, enantiomer, diastereorner, racemate, hydrate, solvate, orsalt thereof, or a mixture of any of the foregoing.
 10. The compoundaccording to claim 1, wherein A is an optionally substituted 5- or6-membered heteroaryl; R¹ is C₁-C₄-alkyl; R² is —C₂-C₃-alkyl-OR⁴,—CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl, —C₂)_(q)-(4- to 6-memberedheterocycloalkyl), or —C₂-C₄-alkynyl, wherein said—CH₂—(C₃-C₄-cycloalkyl), C₃-C₄-cycloalkyl and —(CH₂)_(q)-(4- to6-membered heterocycloalkyl) are optionally substituted with one or moresubstituents which are the same or different, at any ring carbon atom,and wherein any ring nitrogen atom, if present in said —(CH₂)_(q)-(4- to6-membered heterocycloalkyl), is independently substituted with R^(c);R³ is C₁-C₄-alkyl; and q is an integer of 0, or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or salt thereof, or a mixtureof any of the foregoing.
 11. The compound according to claim 1, whereinA is 5- or 6-membered heteroaryl containing at least one or two nitrogenatom(s), wherein said 5- or 6-membered heteroaryl is optionallysubstituted one or two times, identically or differently, with asubstituent selected from the group consisting of a fluorine atom, achlorine atom, C₁-C₂-alkyl optionally substituted with 1-5 fluorineatoms, and C₁-C₂-alkoxy optionally substituted with 1-5 fluorine atoms;R¹ is methyl or ethyl; R² is —C₂-C₃-alkyl-OR⁴, unsubstituted—CH₂—(C₃-C₄-cycloalkyl), unsubstituted C₃-C₄-cycloalkyl, unsubstituted(CH₂)_(q)-(4- to 6-membered heterocycloalkyl), or —C₂-C₄-alkynyl; q isan integer of 0; and R³ is methyl, or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or salt thereof, or a mixtureof any of the foregoing.
 12. The compound according to claim 1, whereinA is pyrimidinyl, pyridazinyl, pyridinyl, pyrazinyl, thiazolyl orthiadiazolyl, each of which is optionally substituted, or an isomer,enantiomer, diastereomer, racemate, hydrate, solvate, or salt thereof,or a mixture of any of the foregoing.
 13. The compound according toclaim 1, wherein A is CF₃-pyrimidinyl, or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or salt thereof, or a mixtureof any of the foregoing.
 14. The compound according to claim 1, whereinR² is cyclopropylmethyl, tetrahydrofuran-3-yl,tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, prop-2-yn-1-yl,but-2-yn-1-yl, oxetan-3-yl, tetrahydropyran-4-yl,tetrahydro-2H-pyran-4-ylmethyl, pyridin-4-yl, pyridin-3-yl,1,3,4-thiadiazol-2-yl, 1,3-thiazol-2-yl, 2,2-dimethyl-2-methoxyethyl,methoxyethyl, piperidin-4-yl, pyrrolidin-3-yl or azetidin-3-yl, each ofwhich is optionally substituted, or an isomer, enantiomer, diastereomer,racemate, hydrate, solvate, or salt thereof, or a mixture of any of theforegoing.
 15. The compound according to claim 1, wherein R² isunsubstituted tetrahydrofuran-3-yl or unsubstituted oxetan-3-yl, or anisomer, enantiomer, diastereomer, racemate, hydrate, solvate, or saltthereof, or a mixture of any of the foregoing.
 16. The compoundaccording to claim 1, wherein R² is —(CH₂)_(q)-(4- to 6-memberedheterocycloalkyl), wherein said (CH₂)_(q)-(4- to 6-memberedheterocycloalkyl) is optionally substituted with one or moresubstituents which are the same or different, at any ring carbon atom,and wherein any ring nitrogen atom, if present in said —(CH₂)_(q)-(4- to6-membered heterocycloalkyl), is independently substituted with R^(c);and q is an integer of 1, or an isomer, enantiomer, diastereomer,racemate, hydrate_solvate, or salt thereof, or a mixture of any of theforegoing.
 17. The compound according to claim 16, wherein R² is—(CH₂)_(q)-morpholinyl substituted with R^(c), or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or salt thereof, or a mixtureof any of the foregoing.
 18. The compound according to claim 17, whereinR² is (4-methylmorpholin-2-yl)methyl, or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or salt thereof, or a mixtureof any of the foregoing.
 19. The compound according to claim 1, whereinR² is —C₂-C₄-alkyl-OH; and R¹ is halogen, or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or salt thereof, or a mixtureof any of the foregoing.
 20. The compound according to claim 1, whereinR² is 3-hydroxybutan 2-yl or an isomer, enantiomer, diastereomer,racemate, hydrate, solvate, or salt thereof, or a mixture of any of theforegoing.
 21. The compound according to claim 16, wherein A ispyrimidinyl or pyridazinyl, each of which is optionally substituted withone or two substituents which are the same or different, and selectedfrom the group consisting of a fluorine atom, a chlorine atom,C₁-C₂-alkyl optionally substituted with 1 to 5 fluorine atoms, andC₁-C₂-alkoxy optionally substituted with 1 to 5 fluorine atoms, or anisomer, enantiomer, diastereomer, racemate, hydrate, solvate, or saltthereof, or a mixture of any of the foregoing.
 22. The compoundaccording to claim 1, which is Trans Isomer 2:3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide; Trans Isomer 1:3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide; Trans Isomer 1:3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide; Cis Isomer 1:3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy)-N-{(1R)-1-[2-(trifluoromethy)pyrimidin-5-yl]ethyl}benzamide; Cis Isomer 2:3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide; Trans Isomer 2:3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide; Cis Isomer 1:3-[(-3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide; Cis Isomer 2:3-[(-3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide; Cis Isomer 1:3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluormethyl)pyrimidin-5-yl]ethyl}benzamide; or Cis Isomer 2:3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide or a hydrate, solvate, or salt thereof, or a mixture of any ofthe foregoing.
 23. The compound according to claim 22, which is CisIsomer 1:3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide or a hydrate, solvate, or salt thereof, or a mixture of any ofthe foregoing.
 24. The compound according to claim 1 or a salt thereof.25. A pharmaceutical composition comprising the compound according toclaim 1, or an isomer, enantiomer, diastereomer, racemate, hydrate,solvate, or salt thereof, or a mixture of any of the foregoing, and apharmaceutically acceptable diluent or carrier.
 26. The pharmaceuticalcomposition according to claim 25, comprising the compound of formula(I) or a salt thereof.
 27. A method of inhibiting P2X3 homomericreceptor in a patient in need thereof, comprising administering aneffective amount of the compound according to claim 1, or an isomer,enantiomer, diastereomer, racemate, hydrate, solvate, or salt thereof,or a mixture of any of the foregoing, to the patient.
 28. The methodaccording to claim 27, comprising administering the compound of formula(I) or a salt thereof.
 29. A method of treating a disease, condition, ordisorder in a patient in need thereof, comprising administering aneffective amount of the compound of claim 1, or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or salt thereof, or a mixtureof any of the foregoing, to the patient, wherein the disease, condition,or disorder is bladder outlet obstruction, urinary incontinence, reducedbladder capacity, increased frequency of micturition, urge incontinence,stress incontinence, bladder hyperreactivity, benign prostatichypertrophy, prostatic hyperplasia, detrusor hyperreflexia, overactivebladder, increased urinary frequency, nocturia, urinary urgency,urethritis, prostatitis, prostatodynia, cystitis, idiopathic bladderhypersensitivity, or hyperalgesia.
 30. The method according to claim 29,comprising administering the compound of formula (I) or a salt thereof.31. A method of treating a disease, condition, or disorder in a patientin need thereof, comprising administering an effect amount of thecompound according to claim 1, or an isomer, enantiomer, diastereomer,racemate, hydrate, solvate, or salt thereof, or a mixture of any of theforegoing, to the patient, wherein the disease, condition, or disorderis endometriosis, dysmenorrhea, dyspareunia, dysuria, or dyschezia. 32.The method according to claim 31, comprising administering the compoundof formula (I) or a salt thereof.
 33. A method of treating pain in apatient in need thereof, comprising administering an effective amount ofthe compound according to claim 1, or an isomer, enantiomer,diastereomer, racemate, hydrate, solvate, or salt thereof, or a mixtureof any of the foregoing, to the patient.
 34. The method according toclaim 33, comprising administering the compound of formula (I) or a saltthereof.